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RS60128B1 - BIARYLIC DERIVATIVES AS GPR120 AGONISTS - Google Patents

BIARYLIC DERIVATIVES AS GPR120 AGONISTS

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Publication number
RS60128B1
RS60128B1 RS20200286A RSP20200286A RS60128B1 RS 60128 B1 RS60128 B1 RS 60128B1 RS 20200286 A RS20200286 A RS 20200286A RS P20200286 A RSP20200286 A RS P20200286A RS 60128 B1 RS60128 B1 RS 60128B1
Authority
RS
Serbia
Prior art keywords
difluoro
butyric acid
phenoxy
pyridin
pyridyl
Prior art date
Application number
RS20200286A
Other languages
Serbian (sr)
Inventor
Young Kwan Kim
Sang Yun Park
Hyun Woo Joo
Eun Sil Choi
Original Assignee
Lg Chemical Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lg Chemical Ltd filed Critical Lg Chemical Ltd
Publication of RS60128B1 publication Critical patent/RS60128B1/en
Publication of RS60128B9 publication Critical patent/RS60128B9/en

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Description

[0001] Opis[0001] Description

[0003] Tehnička oblast[0003] Technical field

[0005] Ovaj pronalazak se odnosi na nove biarilne derivate kao GPR120 agoniste, postupak za pripremu istih, farmaceutsku kompoziciju koja obuhvata iste kao aktivne komponente i njihovu upotrebu. GPR120 agonist ovde označava jedinjenje koje može biti efektivno upotrebljeno za sprečavanje ili lečenje dijabetesa, komplikacija dijabetesa, gojaznosti, nealkoholne masne jetre, steatohepatitisa, osteoporoze ili zapaljenja, promovisanjem GLP-1 u gastrointestinalnom traktu i antizapaljenskim dejstvom.[0005] This invention relates to new biaryl derivatives as GPR120 agonists, a process for their preparation, a pharmaceutical composition comprising the same as active components and their use. GPR120 agonist herein refers to a compound that can be effectively used to prevent or treat diabetes, complications of diabetes, obesity, nonalcoholic fatty liver disease, steatohepatitis, osteoporosis, or inflammation by promoting GLP-1 in the gastrointestinal tract and having an anti-inflammatory effect.

[0007] Stanje tehnike[0007] State of the art

[0009] Dijabetes je podeljen na dva tipa tj., insulin zavisni tip 1 dijabetes i insulin-nezavisni (insulin otporni) tip 2 dijabetes koji je zastupljen kod 90% ili više pacijenata koji boluju od dijabetesa.[0009] Diabetes is divided into two types, ie, insulin-dependent type 1 diabetes and insulin-independent (insulin-resistant) type 2 diabetes, which is present in 90% or more of patients suffering from diabetes.

[0010] Poznato je da GPR120 agonisti, koji su prepoznati kao moguća terapija za dijabetes tip 2, imaju (1) antidijabetsko dejstvo uzrokovano delovanjima rastućeg hormona inkretina u intestinalnim ćelijama, (2) antizapaljensko dejstvo u makrofagovima, i (3) dejstvo poboljšanja insulinske otpornosti u lipocitima. Takođe su poznati kao moguća terapija za dijabetes tip 1 usled poboljšanja proliferacije ćelija pankreasa antizapaljenskim dejstvom.[0010] It is known that GPR120 agonists, which are recognized as a possible therapy for type 2 diabetes, have (1) antidiabetic effects caused by the actions of incretin growth hormone in intestinal cells, (2) anti-inflammatory effects in macrophages, and (3) effects of improving insulin resistance in lipocytes. They are also known as a possible therapy for type 1 diabetes due to the improvement of pancreatic cell proliferation through anti-inflammatory effects.

[0011] G protein-kuplovani receptor 120 (GPR120) je obilno eksprimiran u crevima, plućima, masnom tkivu i makrofagovima koji izazivaju zapaljenje, i aktivira ga slobodna masna kiselina dugog lanca (FFA). GPR120 stimuliše izlučivanje peptida-1 (GLP-1) poput glukagona preko FFA. GLP-1, hormon inkretina, je poznat da stimuliše izlučivanje insulina u pankreasu u zavisnosti od nivoa glukoze u krvi, kao i da ima efekat na poboljšanje insulinske otpornosti, proliferaciju β-ćelija, gubitak apetita i povećanje sitosti. U novije vreme, poznato je da je GPR120 povezan sa poboljšanjem insulinske otpornosti i antizapaljenskim efektom, i stoga se smatra ciljem za razvijanje leka koji će efektivno poboljšati insulinsku otpornost, dijabetes tip 2 i gojaznost koja uključuje manje hronično zapaljenje. Dalje, u eksperimentima na životinjama dijabetesa tip 1, prijavljeno je da GPR120 agonisti poboljšavaju izlučivanje insulina putem proliferacije β-ćelija.[0011] G protein-coupled receptor 120 (GPR120) is abundantly expressed in the intestine, lung, adipose tissue, and inflammatory macrophages, and is activated by long-chain free fatty acid (FFA). GPR120 stimulates secretion of glucagon-like peptide-1 (GLP-1) via FFA. GLP-1, an incretin hormone, is known to stimulate pancreatic insulin secretion in response to blood glucose levels, as well as to have effects on improving insulin resistance, β-cell proliferation, loss of appetite, and increased satiety. More recently, GPR120 is known to be associated with improving insulin resistance and anti-inflammatory effects, and is therefore considered a target for developing a drug that will effectively improve insulin resistance, type 2 diabetes, and obesity involving less chronic inflammation. Furthermore, in type 1 diabetic animal experiments, GPR120 agonists have been reported to improve insulin secretion via β-cell proliferation.

[0012] Pošto GPR 120 agonisti takođe imaju antizapaljensko dejstvo, prijavljeni su kao moguća terapija za bolesti koje su povezane sa zapaljenjem, na primer, steatohepatitis, reumatoidni artritis, itd.[0012] Since GPR 120 agonists also have anti-inflammatory effects, they have been reported as a possible therapy for diseases associated with inflammation, for example, steatohepatitis, rheumatoid arthritis, etc.

[0013] Uzimajući u obzir gore navedeno, istraživanja o GPR120 agonistima aktivno napreduju. Kod reprezentativnih jedinjenja predstavljenih kao GPR120 agonisti, dve arilne grupe su povezane sa centralnom strukturom mosta, a ono što je karakteristično je da je jedna od te dve arilne grupe supstituisana karboksilnom kiselinom. Jedinjenja GPR120 agonista su otkrivena u WO2011/159297, WO2010/080537, WO2010/104195, WO2010/048207, WO2009/147990, WO2008/06 6131, WO2008/103500 i WO2008/139879.[0013] Considering the above, research on GPR120 agonists is actively progressing. In representative compounds presented as GPR120 agonists, two aryl groups are connected to the central bridge structure, and what is characteristic is that one of those two aryl groups is substituted with a carboxylic acid. GPR120 agonist compounds are disclosed in WO2011/159297, WO2010/080537, WO2010/104195, WO2010/048207, WO2009/147990, WO2008/06 6131, WO2008/103500 and WO2008/139879.

[0015] Otkrivanje pronalaska[0015] Disclosure of the Invention

[0016] Tehnički problem[0016] Technical problem

[0017] Predmet ovog pronalaska je da obezbedi nove biarilne derivate kao GPR120 agoniste.[0017] The object of this invention is to provide new biaryl derivatives as GPR120 agonists.

[0018] Drugi predmet ovog pronalaska je da se obezbedi postupak za pripremu biarilnih derivata.[0018] Another object of this invention is to provide a process for the preparation of biaryl derivatives.

[0019] Sledeći predmet ovog pronalaska je da se obezbedi farmaceutska kompozicija za sprečavanje i lečenje dijabetesa, komplikacija dijabetesa, gojaznosti, nealkoholne masne jetre, steatohepatitisa, osteoporoze ili zapaljenja koja kao aktivne komponente obuhvata biarilnederivate, i postupak za pripremu kompozicije.[0019] The next object of this invention is to provide a pharmaceutical composition for the prevention and treatment of diabetes, complications of diabetes, obesity, non-alcoholic fatty liver, steatohepatitis, osteoporosis or inflammation, which includes biaryl derivatives as active components, and a method for preparing the composition.

[0020] Još jedan predmet ovog pronalaska je da obezbedi farmaceutsku kompoziciju za upotrebu u sprečavanju i lečenju dijabetesa, komplikacija dijabetesa, gojaznosti, nealkoholne masne jetre, steatohepatitisa, osteoporoze ili zapaljenja pri čemu kompozicija obuhvata biarilne derivate kao aktivne komponente.Another object of the present invention is to provide a pharmaceutical composition for use in the prevention and treatment of diabetes, complications of diabetes, obesity, non-alcoholic fatty liver disease, steatohepatitis, osteoporosis or inflammation, wherein the composition comprises biaryl derivatives as active components.

[0022] Rešenje problema[0022] Problem solving

[0023] Stoga se ovo otkrivanje bavi biarilnim derivatima formule 1, ili njihovim farmaceutski prihvatljivim solima ili izomerima:[0023] Therefore, this disclosure relates to biaryl derivatives of formula 1, or pharmaceutically acceptable salts or isomers thereof:

[0025] [0025]

[0027] u kojoj,[0027] in which,

[0028] A i B nezavisno predstavljaju fenil ili piridin,[0028] A and B independently represent phenyl or pyridine,

[0029] bilo koje od R<1>-D- i R<2>-E- ne može da postoji, D i E nezavisno predstavljaju ugljenik, azot, kiseonik ili sumpor, ili predstavljaju direktnu vezu, i bilo koje R<1>i R<2>ne može da postoji, ili R<1>i R<2>nezavisno predstavljaju vodonik, halogen, opciono supstituisani C<1>-C<6>-alkil, C<3>-C<10>-cikloalkil, C<2>-C<6>-alkenil, C<2>-C<6>-alkinil, C<3>-C<10>-cikloalkil, C<1>-C<6>-alkil-C<3>-C<10>-cikloalkil, C<1>-C<6>-alkil-C<3>-C<10>-heterocikloalkil, aril, C<1>-C<6>-alkilaril, heteroaril ili C<1>-C<6>-alkil-C<5>-C<6>-heteroaril, a kada D i E predstavljaju azot ili ugljenik, R<1>i R<2>mogu da predstavljaju dva ili tri opciono supstituisana C<1>-C<6>-alkila, C<3>-C<10>-cikloalkila, C<2>-C<6>-alkenila, C<2>-C<6>-alkinila, C<1>-C<6>-alkil-C<3>-C<10>-cikloalkila, arila ili C<1>-C<6>-alkilarila koji mogu biti isti ili različiti, G predstavlja -J-(CR<5>R<6>)<p>, pri čemu J predstavlja kiseonik ili sumpor, R<5>i R<6>nezavisno predstavljaju vodonik, halogen, opciono supstituisani alkil ili cikloalkil, hidroksil ili amin, a R<5>i R<6>koji su supstituisani na istom ili različitom ugljeniku mogu biti povezani kako bi se formirao opciono supstituisani cikloalkil ili cikloheteroalkil,[0029] any of R<1>-D- and R<2>-E- cannot exist, D and E independently represent carbon, nitrogen, oxygen or sulfur, or represent a direct bond, and any R<1> and R<2> cannot exist, or R<1> and R<2> independently represent hydrogen, halogen, optionally substituted C<1>-C<6>-alkyl, C<3>-C<10>-cycloalkyl, C<2>-C<6>-alkenyl, C<2>-C<6>-alkynyl, C<3>-C<10>-cycloalkyl, C<1>-C<6>-alkyl-C<3>-C<10>-cycloalkyl, C<1>-C<6>-alkyl-C<3>-C<10>-heterocycloalkyl, aryl, C<1>-C<6>-alkylaryl, heteroaryl or C<1>-C<6>-alkyl-C<5>-C<6>-heteroaryl, and when D and E represent nitrogen or carbon, R<1> and R<2> may represent two or three optionally substituted C<1>-C<6>-alkyl, C<3>-C<10>-cycloalkyl, C<2>-C<6>-alkenyl, C<2>-C<6>-alkynyl, C<1>-C<6>-alkyl-C<3>-C<10>-cycloalkyl, aryl or C<1>-C<6>-alkylaryl which may be the same or different, G represents -J-(CR<5>R<6>)<p>, wherein J represents oxygen or sulfur, R<5> and R<6> independently represent hydrogen, halogen, optionally substituted alkyl or cycloalkyl, hydroxyl or amine, and R<5> and R<6> which are substituted on the same or different carbons may be linked to form an optionally substituted cycloalkyl or cycloheteroalkyl,

[0030] R<3>i R<4>ne mogu nezavisno da postoje u zavisnosti od broja m ili n, ili da nezavisno predstavljaju vodonik, halogen ili opciono supstituisani C<1>-C<6>-alkil ili C<1>-C<6>-alkoksi,[0030] R<3> and R<4> cannot independently exist depending on the number of m or n, or independently represent hydrogen, halogen or optionally substituted C<1>-C<6>-alkyl or C<1>-C<6>-alkoxy,

[0031] R<7>predstavlja vodonik, alkil ili cikloalkil,[0031] R<7> represents hydrogen, alkyl or cycloalkyl,

[0032] m i n nezavisno predstavljaju ceo broj 0 do 5, i[0032] m and n independently represent an integer from 0 to 5, i

[0033] p predstavlja ceo broj od 1 do 6.[0033] p represents an integer from 1 to 6.

[0034] Jedinjenja formule 1 mogu da formiraju farmaceutski prihvatljive soli, koje uključuju soli sa dodatkom kiseline koje su formirane od neorganskih kiselina kao što su hlorovodonična kiselina, sumporna kiselina, azotna kiselina, fosforna kiselina, bromovodonična kiselina i jodovodonična kiselina; organskih kiselina kao što su vinska kiselina, mravlja kiselina, limunska kiselina, sirćetna kiselina, trihlorosirćetna kiselina, trifluorosirćetna kiselina, glukonska kiselina, benzojeva kiselina, mlečna kiselina, fumarinska kiselina, maleinska kiselina i salicijalna kiselina; ili sulfokiseline kao što su metansulfokiselina, etansulfonkiselina, benzensulfonkiselina i p-toluensulfonkiselina, koje formiraju netoksične soli sa dodatkom kiseline uključujući farmaceutski prihvatljive anjone. Ne primer, farmaceutski prihvatljive soli karboksilne kiseline uključuju soli sa alkalnim metalom ili alkalnim zemljanim metalom kao što je litijum, natrijum, kalijum, kalcijum i magnezijum; soli sa aminokiselinom kao što su lizin, arginin i gvandinin; organske soli kao što je dicikloheksilamin, N-metil-D-glukamin, tris(hidroksimetil)metilamin, dietanolamin, holin i trietilamin. Jedinjenja formule 1 prema ovom pronalasku mogu biti pretvorena u svoje soli primenom konvencionalnih postupaka.[0034] Compounds of formula 1 can form pharmaceutically acceptable salts, which include acid addition salts formed from inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydroiodic acid; organic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid and salicylic acid; or sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, which form non-toxic acid addition salts including pharmaceutically acceptable anions. By way of example, pharmaceutically acceptable salts of the carboxylic acid include alkali metal or alkaline earth metal salts such as lithium, sodium, potassium, calcium and magnesium; salts with amino acids such as lysine, arginine and guandinine; organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline and triethylamine. The compounds of formula 1 according to the present invention can be converted into their salts using conventional procedures.

[0035] Dalje, pošto jedinjenja formule 1 mogu da imaju asimetričan centar ugljenika i asimetričnu osu ili ravan, mogu da postoje kao E- ili Z-izomer, R- ili S-izomer, racemske mešavine ili dijastereoizomerne mešavine i pojedinačan dijasteromer.[0035] Further, since compounds of formula 1 may have an asymmetric carbon center and an asymmetric axis or plane, they may exist as an E- or Z-isomer, an R- or S-isomer, racemic mixtures or diastereoisomeric mixtures, and a single diastereomer.

[0036] Ovde, ukoliko nije drugačije naznačeno, izraz "jedinjenja formule 1" se koristi da označi sva jedinjenja formule 1, uključujući njihove farmaceutski prihvatljive soli i izomere.[0036] Herein, unless otherwise indicated, the term "compounds of formula 1" is used to refer to all compounds of formula 1, including pharmaceutically acceptable salts and isomers thereof.

[0037] Izrazi koji se ovde upotrebljavaju su definisani u nastavku.[0037] The terms used herein are defined below.

[0038] Halogen ili halo znači fluorid (F), hlorin (Cl), bromin (Br) ili jod (I).[0038] Halogen or halo means fluoride (F), chlorine (Cl), bromine (Br) or iodine (I).

[0039] Alkil označava normalne ili razgranate ugljovodonike, i poželjno C<1>-C<6>-alkil. Primeri alkila uključuju, ali bez ograničenja na, metil, etil, n-propil, i-propil, n-butil, i-butil, tert-butil, acetilen, vinil, trifluorometil i njima slične.[0039] Alkyl denotes normal or branched hydrocarbons, and preferably C<1>-C<6>-alkyl. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, acetylene, vinyl, trifluoromethyl, and the like.

[0040] Cikloalkil označava delimično ili potpuno zasićene jednodelne ili kondenzovane ugljovodonike u prstenu, a to je poželjno C<3>-C<10>-cikloalkil, Primeri cikloalkila uključuju, ali bez ograničenja na, ciklopropil, ciklobutil, ciklopentil, cikloheksil, cikloheksenil i njima slične.[0040] Cycloalkyl refers to partially or fully saturated one-membered or fused ring hydrocarbons, preferably C<3>-C<10>-cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and the like.

[0041] Aril označava aromatične ugljovodonike, poželjno C<5>-C<10>-aril, i uključuje, ali bez ograničenja na, fenil, naftil i njima slične.[0041] Aryl refers to aromatic hydrocarbons, preferably C<5>-C<10>-aryl, and includes, but is not limited to, phenyl, naphthyl and the like.

[0042] Heteroaril označava aromatične ugljovodonike koji formiraju jednodelni ili kondenzovani prsten uključujući najmanje jedan heteroatom izabran između N, O i S, a to je poželjno C<3>-C<9>-heteroaril. Primeri heteroarila uključuju, ali bez ograničenja na, piridinil, pirimidinil, piridazinil, oksadijazolil, izoksadijazolil, tetrazolil, trijazolil, indolil, izoksazolil, oksazolil, tijazolil, imidazolil, tiofenil, benztijazole, benzimidazol, 1,2,3,4-tetrahidroizokvinolil, tijazolopiridil i njima slične.[0042] Heteroaryl means aromatic hydrocarbons forming a single or fused ring including at least one heteroatom selected from N, O and S, preferably C<3>-C<9>-heteroaryl. Examples of heteroaryl include, but are not limited to, pyridinyl, pyrimidinyl, pyridazinyl, oxadiazolyl, isoxadiazolyl, tetrazolyl, triazolyl, indolyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, thiophenyl, benzthiazole, benzimidazole, 1,2,3,4-tetrahydroisoquinolyl, thiazolopyridyl, and the like.

[0043] Heterociklil označava delimično ili potpuno zasićene ugljovodonike koji formiraju jednodelni ili kondenzovani prsten uključujući najmanje jedan heteroatom izabran između N, O i S, a to je poželjno C<3>-C<10>-heterociklil. Primeri heterociklila uključuju, ali bez ograničenja na, pirolidinil, piperidinil, morfolinil, imidazolinil, piperazinil, tetrahidrofuran, tetrahidrotiofuran i njima slične.[0043] Heterocyclyl denotes partially or fully saturated hydrocarbons forming a single or fused ring including at least one heteroatom selected from N, O and S, preferably C<3>-C<10>-heterocyclyl. Examples of heterocyclyl include, but are not limited to, pyrrolidinyl, piperidinyl, morpholinyl, imidazolinyl, piperazinyl, tetrahydrofuran, tetrahydrothiofuran, and the like.

[0044] Arilalkil i heteroarilalkil označavaju grupe koje su formirane kombinacijom gore pomenutog arila sa alkilom ili heteroarila sa alkilom. Primeri uključuju, ali bez ograničenja na, benzil, tiofenmetil, pirimidin metil i njima slične.[0044] Arylalkyl and heteroarylalkyl denote groups formed by the combination of the above-mentioned aryl with alkyl or heteroaryl with alkyl. Examples include, but are not limited to, benzyl, thiophenemethyl, pyrimidine methyl, and the like.

[0045] Gore pomenuti amin, alkil, cikloalkil, aril, heteroaril, heterociklil, arilalkil i heteroarilalkil mogu biti supstituisani najmanje jednom grupom izabranom između sledećih grupa: alkil, cikloalkil, heterociklil, aril, heteroaril, arilalkil, heteroarilalkil, heterociklilalkil, okso, cijano, halo, nitro, -OR, -OC(O)R, -OC(O)OR, SR, -S(O)R, -S(O)<2>R, -C(O)R, -C(O)OR, -C(S)R, -C(O)NRR, -NR<2>, -NRCHO, - NRC(O)R, -NRC(O)NRR, -C(S)NRR, -NRC(S)R i -NRC(S)NRR, pre čemu je R nezavisno izabran iz grupe koju čine vodonik, alkil, cikloalkil, heterociklil, aril, heteroaril, arilalkil i heteroarilalkil, a kada su dva Rs supstituisana, mogu biti povezani da bi se dobio cikloalkil ili heterociklil.[0045] The above-mentioned amine, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl and heteroarylalkyl may be substituted with at least one group selected from the following groups: alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, oxo, cyano, halo, nitro, -OR, -OC(O)R, -OC(O)OR, SR, -S(O)R, -S(O)<2>R, -C(O)R, -C(O)OR, -C(S)R, -C(O)NRR, -NR<2>, -NRCHO, - NRC(O)R, -NRC(O)NRR, -C(S)NRR, -NRC(S)R and -NRC(S)NRR, where R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, and when two Rs are substituted, they can be linked to give cycloalkyl or heterocyclyl.

[0046] Ovaj pronalazak je definisan u zahtevima i odnosi se na sledeća jedinjenja:[0046] This invention is defined in the claims and relates to the following compounds:

[0047] 4-[4-(6-fenoksi-2-piridil)fenoksi]buterna kiselina;[0047] 4-[4-(6-phenoxy-2-pyridyl)phenoxy]butyric acid;

[0048] 4-[2,6-difluoro-4-(6-izopropilsulfanil-2-piridil)fenoksi]buterna kiselina;[0048] 4-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]butyric acid;

[0049] 4-[2,6-difluoro-4-(6-fenoksi-2-piridil)fenoksi]buterna kiselina;[0049] 4-[2,6-difluoro-4-(6-phenoxy-2-pyridyl)phenoxy]butyric acid;

[0050] 4-[2-hloro-4-(6-izopropilsulfanil-2-piridil)fenoksi]buterna kiselina;[0050] 4-[2-chloro-4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]butyric acid;

[0051] 4-[2-fluoro-4-(6-izopropilsulfanil-2-piridil)fenoksi]buterna kiselina;[0051] 4-[2-fluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]butyric acid;

[0052] 4-[4-(6-ciklopentilsulfanil-2-piridil)-2,6-difluoro-fenoksi]buterna kiselina;[0052] 4-[4-(6-cyclopentylsulfanyl-2-pyridyl)-2,6-difluoro-phenoxy]butyric acid;

[0053] 4-[4-(2-ciklobutilsulfanil-piridin-3-il)-2-metoksi-fenoksi]-buterna kiselina;[0053] 4-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2-methoxy-phenoxy]-butyric acid;

[0054] 4-[2,6-difluoro-4-(2-izopropilsulfanil-4-piridil)fenoksi]buterna kiselina;[0054] 4-[2,6-difluoro-4-(2-isopropylsulfanyl-4-pyridyl)phenoxy]butyric acid;

[0055] 4-[4-[6-(ciklopentoksi)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina;[0055] 4-[4-[6-(cyclopentoxy)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid;

[0056] 4-[4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-dimetil-fenoksi]-buterna kiselina;[0056] 4-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-dimethyl-phenoxy]-butyric acid;

[0057] 4-[4-[3-(ciklopentoksi)fenil]-2,6-difluoro-fenoksi]buterna kiselina;[0057] 4-[4-[3-(cyclopentoxy)phenyl]-2,6-difluoro-phenoxy]butyric acid;

[0058] 4-[2,6-difluoro-4-(6-pirolidin-1-il-2-piridil)fenoksilbuterna kiselina;[0058] 4-[2,6-difluoro-4-(6-pyrrolidin-1-yl-2-pyridyl)phenoxybutyric acid;

[0059] 4-[4-(2-sec-butilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;[0059] 4-[4-(2-sec-butylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid;

[0060] -[4-[3-(ciklopentoksi)fenil]-2,3-difluoro-fenoksi]buterna kiselina;[0060] -[4-[3-(cyclopentoxy)phenyl]-2,3-difluoro-phenoxy]butyric acid;

[0061] -[2,6-difluoro-4-[6-(1-piperidil)-2-piridil]fenoksi]buterna kiselina;[0061] -[2,6-difluoro-4-[6-(1-piperidyl)-2-pyridyl]phenoxy]butyric acid;

[0062] -[4-(6-anilino-2-piridil)-2,6-difluoro-fenoksi]buterna kiselina;[0062] -[4-(6-anilino-2-pyridyl)-2,6-difluoro-phenoxy]butyric acid;

[0063] -[2,6-difluoro-4-[6-(N-metilanilino)-2-piridil]fenoksi]buterna kiselina;[0063] -[2,6-difluoro-4-[6-(N-methylanilino)-2-pyridyl]phenoxy]butyric acid;

[0064] -[4-[6-(ciklopentilamino)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina;[0064] -[4-[6-(cyclopentylamino)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid;

[0065] -[4-[6-(ciklopropilmetilsulfanil)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina;[0065] -[4-[6-(cyclopropylmethylsulfanyl)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid;

[0066] -[4-(6-ciklobutilsulfanil-2-piridil)-2,6-difluoro-fenoksi]buterna kiselina;[0066] -[4-(6-cyclobutylsulfanyl-2-pyridyl)-2,6-difluoro-phenoxy]butyric acid;

[0067] -[2,6-difluoro-4-(6-propilsulfanil-2-piridil)fenoksi]buterna kiselina;[0067] -[2,6-difluoro-4-(6-propylsulfanyl-2-pyridyl)phenoxy]butyric acid;

[0068] -[2,6-difluoro-4-(6-izopropoksi-2-piridil)fenoksi]buterna kiselina;[0068] -[2,6-difluoro-4-(6-isopropoxy-2-pyridyl)phenoxy]butyric acid;

[0069] -[2,6-difluoro-4-(6-propoksi-2-piridil)fenoksi]buterna kiselina;[0069] -[2,6-difluoro-4-(6-propoxy-2-pyridyl)phenoxy]butyric acid;

[0070] -[4-[6-(ciklopropilmetoksi)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina;[0070] -[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid;

[0071] -[4-[6-(ciklobutoksi)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina;[0071] -[4-[6-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid;

[0072] -[4-[6-(ciklobutoksi)-2-piridil]-2-metil-fenoksi]buterna kiselina;[0072] -[4-[6-(cyclobutoxy)-2-pyridyl]-2-methyl-phenoxy]butyric acid;

[0073] -[4-[6-(ciklobutoksi)-2-piridil]-2-(trifluorometil)fenoksi]buterna kiselina;[0073] -[4-[6-(cyclobutoxy)-2-pyridyl]-2-(trifluoromethyl)phenoxy]butyric acid;

[0074] -[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]valerijanska kiselina;[0074] -[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]valeric acid;

[0075] -[4-[6-(ciklobutoksi)-2-piridil]-2,6-difluoro-fenoksi]valerijanska kiselina;[0075] -[4-[6-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenoxy]valeric acid;

[0076] -[[5-(2-ciklobutilsulfanil-3-piridil)-2-piridil]oksi]valerijanska kiselina;[0076] -[[5-(2-cyclobutylsulfanyl-3-pyridyl)-2-pyridyl]oxy]valeric acid;

[0077] -{2,6-difluoro-4-[2-(3-metil-butilsulfanil)-pindin-3-il]-fenoksi}-buterna kiselina;[0077] -{2,6-difluoro-4-[2-(3-methyl-butylsulfanyl)-pindin-3-yl]-phenoxy}-butyric acid;

[0078] -{2,6-difluoro-4-[2-(2-fluoro-etoksi)-piridin-3-il]-fenoksi}-buterna kiselina;[0078] -{2,6-difluoro-4-[2-(2-fluoro-ethoxy)-pyridin-3-yl]-phenoxy}-butyric acid;

[0079] -[1-[[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]metil] ciklopropil]sirćetna kiselina; -[1-[[4-[3-(ciklobutoksi)fenil]-2,6-difluoro-fenoksi]metil]ciklopropil]sirćetna kiselina;[0079] -[1-[[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]methyl]cyclopropyl]acetic acid; -[1-[[4-[3-(cyclobutoxy)phenyl]-2,6-difluoro-phenoxy]methyl]cyclopropyl]acetic acid;

[0080] -[[6-[3-(ciklobutoksi)fenil]-3-piridil]oksi]buterna kiselina;[0080] -[[6-[3-(cyclobutoxy)phenyl]-3-pyridyl]oxy]butyric acid;

[0081] -[[6-[3-(ciklopentoksi)fenil]-3-piridil]oksi]buterna kiselina;[0081] -[[6-[3-(cyclopentoxy)phenyl]-3-pyridyl]oxy]butyric acid;

[0082] -(2'-fenoksi-bifenil-4-iloksi)-buterna kiselina;[0082] -(2'-phenoxy-biphenyl-4-yloxy)-butyric acid;

[0083] -[4-(2-izopropilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina;[0083] -[4-(2-isopropylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid;

[0084] -(3,5-difluoro-2'-fenoksi-bifenil-4-iloksi)-buterna kiselina;[0084] -(3,5-difluoro-2'-phenoxy-biphenyl-4-yloxy)-butyric acid;

[0085] -[4-(2-ciklopentilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina;[0085] -[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid;

[0086] -[2,6-difluoro-4-(2-izopropilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina;[0086] -[2,6-difluoro-4-(2-isopropylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid;

[0087] -[2,6-difluoro-4-(2-fenoksi-piridin-3-il)-fenoksi]-buterna kiselina;[0087] -[2,6-difluoro-4-(2-phenoxy-pyridin-3-yl)-phenoxy]-butyric acid;

[0088] -[2,6-difluoro-4-(2-izopropoksi-piridin-3-il)-fenoksi]-buterna kiselina;[0088] -[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenoxy]-butyric acid;

[0089] -[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;[0089] -[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid;

[0090] -[4-(2-ciklopentilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;[0090] -[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid;

[0091] -[4-(2-ciklopropilmetoksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;[0091] -[4-(2-cyclopropylmethoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid;

[0092] -[4-(2-ciklopropilmetilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;[0092] -[4-(2-cyclopropylmethylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid;

[0093] -[4-(2-ciklobutilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina;[0093] -[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid;

[0094] -[4-(2-ciklopropilmetilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina; -[4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;[0094] -[4-(2-cyclopropylmethylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid; -[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid;

[0095] -[4-(2-propilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina;[0095] -[4-(2-propylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid;

[0096] -(3,5-difluoro-2'-izopropoksi-bifenil-4-iloksi)-buterna kiselina;[0096] -(3,5-difluoro-2'-isopropoxy-biphenyl-4-yloxy)-butyric acid;

[0097] -(2'-ciklobutoksi-3,5-difluoro-bifenil-4-iloksi)-buterna kiselina;[0097] -(2'-cyclobutoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric acid;

[0098] -(2'-ciklopropilmetoksi-3,5-difluoro-bifenil-4-iloksi)-buterna kiselina;[0098] -(2'-cyclopropylmethoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric acid;

[0099] -(2'-ciklopentiloksi-3,5-difluoro-bifenil-4-iloksi)-buterna kiselina;[0099] -(2'-cyclopentyloxy-3,5-difluoro-biphenyl-4-yloxy)-butyric acid;

[0100] -(2'-ciklopentiloksi-bifenil-4-iloksi)-buterna kiselina;[0100] -(2'-cyclopentyloxy-biphenyl-4-yloxy)-butyric acid;

[0101] -(2'-izopropoksi-bifenil-4-iloksi)-buterna kiselina;[0101] -(2'-isopropoxy-biphenyl-4-yloxy)-butyric acid;

[0102] -(2'-ciklopropilmetoksi-bifenil-4-iloksi)-buterna kiselina;[0102] -(2'-cyclopropylmethoxy-biphenyl-4-yloxy)-butyric acid;

[0103] -[4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-2-metil-buterna kiselina;[0103] -[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-2-methyl-butyric acid;

[0104] -[4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-difluoro-fenoksimetil]-ciklopropan karboksilna kiselina; -[4-(2-ciklobutilsulfanil-piridin-3-il)-2,5-difluoro-fenoksi]-buterna kiselina;[0104] -[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxymethyl]-cyclopropane carboxylic acid; -[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,5-difluoro-phenoxy]-butyric acid;

[0105] -[4-(6-ciklobutilsulfanil-piridin-2-il)-2,5-difluoro-fenoksi]-buterna kiselina;[0105] -[4-(6-cyclobutylsulfanyl-pyridin-2-yl)-2,5-difluoro-phenoxy]-butyric acid;

[0106] -[4-(2-tert-butilsulfanil-piridin-3-il)-2,6-difluoro-fenoksil-buterna kiselina;[0106] -[4-(2-tert-butylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxyl-butyric acid;

[0107] -[2,6-difluoro-4-(2-propilsulfanil-3-piridil)fenoksi]kapronska kiselina;[0107] -[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)phenoxy]caproic acid;

[0108] -{2,6-difluoro-4-[6-(2-metil-propenil)-piridin-2-il]-fenoksi}-buterna kiselina;[0108] -{2,6-difluoro-4-[6-(2-methyl-propenyl)-pyridin-2-yl]-phenoxy}-butyric acid;

[0109] -[2,6-difluoro-4-(6-izobutil-piridin-2-il)-fenoksi]-buterna kiselina;[0109] -[2,6-difluoro-4-(6-isobutyl-pyridin-2-yl)-phenoxy]-butyric acid;

[0110] -[4-(2-ciklobutilsulfanil-piridin-3-il)-3,5-difluoro-fenoksi]-buterna kiselina;[0110] -[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-3,5-difluoro-phenoxy]-butyric acid;

[0111] -{2,6-difluoro-4-[2-(tetrahidro-piran-4-iloksi)-piridin-3-il]-fenoksi}-buterna kiselina;[0111] -{2,6-difluoro-4-[2-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-phenoxy}-butyric acid;

[0112] -{2,6-difluoro-4-[2-(tetrahidro-furan-3-iloksi)-piridin-3-il]-fenoksi}-buterna kiselina;[0112] -{2,6-difluoro-4-[2-(tetrahydro-furan-3-yloxy)-pyridin-3-yl]-phenoxy}-butyric acid;

[0113] -[4-(2-ciklobutoksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;[0113] -[4-(2-cyclobutoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid;

[0114] -{2,6-difluoro-4-[2-(2-metoksi-etoksi)-piridin-3-il]-fenoksi}-buterna kiselina;[0114] -{2,6-difluoro-4-[2-(2-methoxy-ethoxy)-pyridin-3-yl]-phenoxy}-butyric acid;

[0115] -[2,6-difluoro-4-(2-pirolidin-1-il-3-piridil)fenoksi]buterna kiselina;[0115] -[2,6-difluoro-4-(2-pyrrolidin-1-yl-3-pyridyl)phenoxy]butyric acid;

[0116] -[4-[2-(ciklopentilamino)-3-piridil]-2,6-difluoro-fenoksi]buterna kiselina;[0116] -[4-[2-(cyclopentylamino)-3-pyridyl]-2,6-difluoro-phenoxy]butyric acid;

[0117] -[4-[2-(ciklopropilmetilamino)-3-piridil]-2,6-difluoro-fenoksi]buterna kiselina;[0117] -[4-[2-(cyclopropylmethylamino)-3-pyridyl]-2,6-difluoro-phenoxy]butyric acid;

[0118] -[4-[6-(ciklopropilmetilamino)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina;[0118] -[4-[6-(cyclopropylmethylamino)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid;

[0119] -[2,6-difluoro-4-[2-(izopropilamino)-3-piridil]fenoksi]buterna kiselina;[0119] -[2,6-difluoro-4-[2-(isopropylamino)-3-pyridyl]phenoxy]butyric acid;

[0120] -[4-[2-(ciklopropilamino)-3-piridil]-2,6-difluoro-fenoksi]buterna kiselina;[0120] -[4-[2-(cyclopropylamino)-3-pyridyl]-2,6-difluoro-phenoxy]butyric acid;

[0121] -[2,6-difluoro-4-[6-(izopropilamino)-2-piridil]fenoksi]buterna kiselina;[0121] -[2,6-difluoro-4-[6-(isopropylamino)-2-pyridyl]phenoxy]butyric acid;

[0122] -[4-[2-(ciklopentilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina;[0122] -[4-[2-(cyclopentylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid;

[0123] -[4-[3-(ciklopentilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina;[0123] -[4-[3-(cyclopentylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid;

[0124] -[2,6-difluoro-4-[2-(propilamino)fenil]fenoksi]buterna kiselina;[0124] -[2,6-difluoro-4-[2-(propylamino)phenyl]phenoxy]butyric acid;

[0125] -[4-[2-(ciklopropilmetilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina;[0125] -[4-[2-(cyclopropylmethylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid;

[0126] -[2,6-difluoro-4-[2-(izopropilamino)fenil]fenoksi]buterna kiselina;[0126] -[2,6-difluoro-4-[2-(isopropylamino)phenyl]phenoxy]butyric acid;

[0127] -[4-[2-(ciklopentilamino)fenil]fenoksi]buterna kiselina;[0127] -[4-[2-(cyclopentylamino)phenyl]phenoxy]butyric acid;

[0128] -[4-[2-(ciklopropilmetilamino)fenil]fenoksi]buterna kiselina;[0128] -[4-[2-(cyclopropylmethylamino)phenyl]phenoxy]butyric acid;

[0129] 4-[4-[2-(propilamino)fenil]fenoksi]buterna kiselina;[0129] 4-[4-[2-(propylamino)phenyl]phenoxy]butyric acid;

[0130] 4-[4-[2-(izopropilamino)fenil]fenoksi]buterna kiselina;[0130] 4-[4-[2-(isopropylamino)phenyl]phenoxy]butyric acid;

[0131] 4-[4-[2-(ciklobutilamino)fenil]fenoksi]buterna kiselina;[0131] 4-[4-[2-(cyclobutylamino)phenyl]phenoxy]butyric acid;

[0132] 4-[4-[2-(ciklobutilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina;[0132] 4-[4-[2-(cyclobutylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid;

[0133] 4-[4-[3-(ciklopropilmetilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina;[0133] 4-[4-[3-(cyclopropylmethylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid;

[0134] 4-[2,6-difluoro-4-[3-(izopropilamino)fenil]fenoksi]buterna kiselina;[0134] 4-[2,6-difluoro-4-[3-(isopropylamino)phenyl]phenoxy]butyric acid;

[0135] 4-[2,6-difluoro-4-(3-pirolidin-1-ilfenil)fenoksi]buterna kiselina;[0135] 4-[2,6-difluoro-4-(3-pyrrolidin-1-ylphenyl)phenoxy]butyric acid;

[0136] 4-[4-[3-(ciklobutilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina;[0136] 4-[4-[3-(cyclobutylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid;

[0137] 4-[2,6-difluoro-4-[3-(propilamino)fenil]fenoksi]buterna kiselina;[0137] 4-[2,6-difluoro-4-[3-(propylamino)phenyl]phenoxy]butyric acid;

[0138] 4-[4-[5-hloro-2-(ciklopentilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina;[0138] 4-[4-[5-chloro-2-(cyclopentylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid;

[0139] 4-[4-[2-(ciklopentilamino)-5-fluoro-fenil]-2,6-difluoro-fenoksi]buterna kiselina;[0139] 4-[4-[2-(cyclopentylamino)-5-fluoro-phenyl]-2,6-difluoro-phenoxy]butyric acid;

[0140] 4-[4-(3-ciklopentilfenil)-2,6-difluoro-fenoksi]buterna kiselina;[0140] 4-[4-(3-cyclopentylphenyl)-2,6-difluoro-phenoxy]butyric acid;

[0141] 4-[4-[3-(ciklopentilmetil)fenil]-2,6-difluoro-fenoksi]buterna kiselina;[0141] 4-[4-[3-(cyclopentylmethyl)phenyl]-2,6-difluoro-phenoxy]butyric acid;

[0142] 4-[4-[2-(ciklopentilmetil)fenil]-2,6-difluoro-fenoksi]buterna kiselina;[0142] 4-[4-[2-(cyclopentylmethyl)phenyl]-2,6-difluoro-phenoxy]butyric acid;

[0143] 4-[4-[6-(ciklopentilmetil)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina;[0143] 4-[4-[6-(cyclopentylmethyl)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid;

[0144] 4-[4-[2-(ciklobutilmetil)fenil]-2,6-difluoro-fenoksi]buterna kiselina;[0144] 4-[4-[2-(cyclobutylmethyl)phenyl]-2,6-difluoro-phenoxy]butyric acid;

[0145] 4-[4-[3-(ciklobutilmetil)fenil]-2,6-difluoro-fenoksi]buterna kiselina;[0145] 4-[4-[3-(cyclobutylmethyl)phenyl]-2,6-difluoro-phenoxy]butyric acid;

[0146] 4-[4-[6-(ciklobutilmetil)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina;[0146] 4-[4-[6-(cyclobutylmethyl)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid;

[0147] 4-[4-(2-ciklopentilfenil)-2,6-difluoro-fenoksi]buterna kiselina;[0147] 4-[4-(2-cyclopentylphenyl)-2,6-difluoro-phenoxy]butyric acid;

[0148] 4-[4-(6-ciklopentil-2-piridil)-2,6-difluoro-fenoksi]buterna kiselina;[0148] 4-[4-(6-cyclopentyl-2-pyridyl)-2,6-difluoro-phenoxy]butyric acid;

[0149] 4-[2,6-difluoro-4-(2-izobutil-3-piridil)fenoksi]buterna kiselina;[0149] 4-[2,6-difluoro-4-(2-isobutyl-3-pyridyl)phenoxy]butyric acid;

[0150] 4-[4-(2-ciklopentil-3-piridil)-2,6-difluoro-fenoksi]buterna kiselina;[0150] 4-[4-(2-cyclopentyl-3-pyridyl)-2,6-difluoro-phenoxy]butyric acid;

[0151] 4-[4-[2-(ciklopentilmetil)-3-piridil]-2,6-difluoro-fenoksi]buterna kiselina;[0151] 4-[4-[2-(cyclopentylmethyl)-3-pyridyl]-2,6-difluoro-phenoxy]butyric acid;

[0152] 4-[2,6-difluoro-4-(2-pirol-1-il-3-piridil)fenoksi]buterna kiselina;[0152] 4-[2,6-difluoro-4-(2-pyrrol-1-yl-3-pyridyl)phenoxy]butyric acid;

[0153] 4-[2,6-difluoro-4-[2-(4-metilpirazol-1-il)-3-piridil]fenoksi]buterna kiselina;[0153] 4-[2,6-difluoro-4-[2-(4-methylpyrazol-1-yl)-3-pyridyl]phenoxy]butyric acid;

[0154] 4-[2,6-difluoro-4-(2-morfolino-3-piridil)fenoksi]buterna kiselina;[0154] 4-[2,6-difluoro-4-(2-morpholino-3-pyridyl)phenoxy]butyric acid;

[0155] 4-[2,6-difluoro-4-[2-(tetrahidropiran-4-ilmetilamino)-3-piridil]fenoksi] buterna kiselina; 4-[2,6-difluoro-4-[2-(1-piperidil)-3-piridil]fenoksi]buterna kiselina;[0155] 4-[2,6-difluoro-4-[2-(tetrahydropyran-4-ylmethylamino)-3-pyridyl]phenoxy]butyric acid; 4-[2,6-difluoro-4-[2-(1-piperidyl)-3-pyridyl]phenoxy]butyric acid;

[0156] (4S)-4-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]valerijanska kiselina;[0156] (4S)-4-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]valeric acid;

[0157] (4R)-4-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]valerijanska kiselina;[0157] (4R)-4-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]valeric acid;

[0158] (4R)-4-[4-[3-(ciklobutoksi)fenil]-2,6-difluoro-fenoksi]valerijanska kiselina;[0158] (4R)-4-[4-[3-(cyclobutoxy)phenyl]-2,6-difluoro-phenoxy]valeric acid;

[0159] (4R)-4-[4-(2-ciklopentilsulfanil-3-piridil)-2,6-difluoro-fenoksi]valerijanska kiselina; (4R)-4-[2,6-difluoro-4-(3-fenoksifenil)fenoksi]valerijanska kiselina;[0159] (4R)-4-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]valeric acid; (4R)-4-[2,6-difluoro-4-(3-phenoxyphenyl)phenoxy]valeric acid;

[0160] 4-(3'-ciklobutoksi-bifenil-4-ilsulfanil)-buterna kiselina;[0160] 4-(3'-cyclobutoxy-biphenyl-4-ylsulfanyl)-butyric acid;

[0161] 4-(3'-izopropoksi-bifenil-4-ilsulfanil)-buterna kiselina;[0161] 4-(3'-isopropoxy-biphenyl-4-ylsulfanyl)-butyric acid;

[0162] [1-(3,5-difluoro-3'-izopropoksi-bifenil-4-ilsulfanilmetil)-ciklopropil]-sirćetna kiselina; -(3'-ciklopentiloksi-3,5-difluoro-bifenil-4-ilsulfanil)-buterna kiselina;[0162] [1-(3,5-difluoro-3'-isopropoxy-biphenyl-4-ylsulfanylmethyl)-cyclopropyl]-acetic acid; -(3'-cyclopentyloxy-3,5-difluoro-biphenyl-4-ylsulfanyl)-butyric acid;

[0163] -[4-(2-ciklopentiloksi-piridin-3-il)-fenilsulfanil]-buterna kiselina;[0163] -[4-(2-cyclopentyloxy-pyridin-3-yl)-phenylsulfanyl]-butyric acid;

[0164] -[4-(2-ciklopropilmetoksi-piridin-3-il)-fenilsulfanil]-buterna kiselina;[0164] -[4-(2-cyclopropylmethoxy-pyridin-3-yl)-phenylsulfanyl]-butyric acid;

[0165] -(3'-fenoksi-bifenil-4-ilsulfanil)-buterna kiselina;[0165] -(3'-phenoxy-biphenyl-4-ylsulfanyl)-butyric acid;

[0166] -(3'-ciklopentiloksi-bifenil-4-ilsulfanil)-buterna kiselina;[0166] -(3'-cyclopentyloxy-biphenyl-4-ylsulfanyl)-butyric acid;

[0167] -(3'-propoksi-bifenil-4-ilsulfanil)-buterna kiselina;[0167] -(3'-propoxy-biphenyl-4-ylsulfanyl)-butyric acid;

[0168] -[4-(6-ciklobutoksi-piridin-2-il)-fenilsulfanil]-buterna kiselina;[0168] -[4-(6-cyclobutoxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid;

[0169] -[4-(6-ciklopentiloksi-piridin-2-il)-fenilsulfanil]-buterna kiselina;[0169] -[4-(6-cyclopentyloxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid;

[0170] -[4-(6-izopropoksi-piridin-2-il)-fenilsulfanil]-buterna kiselina;[0170] -[4-(6-isopropoxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid;

[0171] -[4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-buterna kiselina;[0171] -[4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-butyric acid;

[0172] -[4-(6-propoksi-piridin-2-il)-fenilsulfanil]-buterna kiselina;[0172] -[4-(6-propoxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid;

[0173] -[4-(6-ciklopentilsulfanil-piridin-2-il)-fenilsulfanil]-buterna kiselina;[0173] -[4-(6-cyclopentylsulfanyl-pyridin-2-yl)-phenylsulfanyl]-butyric acid;

[0174] -(3'-ciklobutoksi-3,5-difluoro-bifenil-4-ilsulfanil)-buterna kiselina;[0174] -(3'-cyclobutoxy-3,5-difluoro-biphenyl-4-ylsulfanyl)-butyric acid;

[0175] -(3,5-difluoro-3'-izopropoksi-bifenil-4-ilsulfanil)-buterna kiselina;[0175] -(3,5-difluoro-3'-isopropoxy-biphenyl-4-ylsulfanyl)-butyric acid;

[0176] -[2,6-difluoro-4-(6-propoksi-piridin-2-il)-fenilsulfanil]-buterna kiselina;[0176] -[2,6-difluoro-4-(6-propoxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid;

[0177] -[2,6-difluoro-4-(6-izopropoksi-piridin-2-il)-fenilsulfanil]-buterna kiselina;[0177] -[2,6-difluoro-4-(6-isopropoxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid;

[0178] -[2,6-difluoro-4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-buterna kiselina;[0178] -[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-butyric acid;

[0179] -[2,6-difluoro-4-(2-propoksi-piridin-3-il)-fenilsulfanil]-buterna kiselina;[0179] -[2,6-difluoro-4-(2-propoxy-pyridin-3-yl)-phenylsulfanyl]-butyric acid;

[0180] -[2,6-difluoro-4-(6-izopropilsulfanil-piridin-2-il)-fenilsulfanil]-buterna kiselina; -[2,6-difluoro-4-(6-propilsulfanil-piridin-2-il)-fenilsulfanil]-buterna kiselina; -[4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina; -[4-(2-ciklobutoksi-piridin-3-il)-fenilsulfanil]-buterna kiselina;[0180] -[2,6-difluoro-4-(6-isopropylsulfanyl-pyridin-2-yl)-phenylsulfanyl]-butyric acid; -[2,6-difluoro-4-(6-propylsulfanyl-pyridin-2-yl)-phenylsulfanyl]-butyric acid; -[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid; -[4-(2-cyclobutoxy-pyridin-3-yl)-phenylsulfanyl]-butyric acid;

[0181] -[4-(2-ciklobutoksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina;[0181] -[4-(2-cyclobutoxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid;

[0182] -[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina; -[2,6-difluoro-4-(2-izopropilsulfanil-piridin-3-il)-fenilsulfanil]-buterna kiselina; -[4-(2-ciklopentilsulfanil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina; -[4-(2-izopropilsulfanil-piridin-3-il)-fenilsulfanil]-buterna kiselina;[0182] -[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid; -[2,6-difluoro-4-(2-isopropylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-butyric acid; -[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid; -[4-(2-isopropylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-butyric acid;

[0183] -[4-(2-ciklopentilsulfanil-piridin-3-il)-fenilsulfanil]-buterna kiselina;[0183] -[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-butyric acid;

[0184] -[2-fluoro-4-(6-izopropoksi-piridin-2-il)-fenilsulfanil]-buterna kiselina;[0184] -[2-fluoro-4-(6-isopropoxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid;

[0185] -[4-(2-ciklopentiloksi-piridin-3-il)-2-fluoro-fenilsulfanil]-buterna kiselina;[0185] -[4-(2-cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric acid;

[0186] -[4-(2-ciklobutilsulfanil-piridin-3-il)-2-fluoro-fenilsulfanil]-buterna kiselina; -[4-(2-ciklobutilsulfanil-piridin-3-il)-fenilsulfanil]-buterna kiselina;[0186] -[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric acid; -[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-butyric acid;

[0187] -[4-(6-ciklobutoksi-piridin-2-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina;[0187] -[4-(6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid;

[0188] -[4-(6-ciklopentiloksi-piridin-2-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina; -[4-(6-ciklobutilsulfanil-piridin-2-il)-fenilsulfanil]-buterna kiselina;[0188] -[4-(6-cyclopentyloxy-pyridin-2-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid; -[4-(6-cyclobutylsulfanyl-pyridin-2-yl)-phenylsulfanyl]-butyric acid;

[0189] -[4-(6-ciklopropilmetoksi-piridin-2-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina; -[4-(6-ciklobutilsulfanil-piridin-2-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina; -[4-(6-ciklopentilsulfanil-piridin-2-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina; -(2'-ciklopentilamino-3-fluoro-bifenil-4-ilsulfanil)-buterna kiselina;[0189] -[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid; -[4-(6-cyclobutylsulfanyl-pyridin-2-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid; -[4-(6-cyclopentylsulfanyl-pyridin-2-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid; -(2'-cyclopentylamino-3-fluoro-biphenyl-4-ylsulfanyl)-butyric acid;

[0190] -(2'-ciklopentilamino-3,5-difluoro-bifenil-4-ilsulfanil)-buterna kiselina;[0190] -(2'-cyclopentylamino-3,5-difluoro-biphenyl-4-ylsulfanyl)-butyric acid;

[0191] -[2'-(ciklopropilmetil-amino)-3,5-difluoro-bifenil-4-ilsulfanil]-buterna kiselina; -[2-fluoro-4-(2-izopropilsulfanil-piridin-3-il)-fenilsulfanil]-buterna kiselina; -[4-(2-ciklopentilsulfanil-piridin-3-il)-2-fluoro-fenilsulfanil]-buterna kiselina; -(3,5-difluoro-2'-izopropilamino-bifenil-4-ilsulfanil)-buterna kiselina;[0191] -[2'-(cyclopropylmethyl-amino)-3,5-difluoro-biphenyl-4-ylsulfanyl]-butyric acid; -[2-fluoro-4-(2-isopropylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-butyric acid; -[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric acid; -(3,5-difluoro-2'-isopropylamino-biphenyl-4-ylsulfanyl)-butyric acid;

[0192] -(3,5-difluoro-2'-propilamino-bifenil-4-ilsulfanil)-buterna kiselina;[0192] -(3,5-difluoro-2'-propylamino-biphenyl-4-ylsulfanyl)-butyric acid;

[0193] -[4-(2-ciklopropilmetoksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina; -[2,6-difluoro-4-(2-propilsulfanil-piridin-3-il)-fenilsulfanil]-buterna kiselina; -[4-(6-ciklobutilsulfanil-piridin-2-il)-2-fluoro-fenilsulfanil]-buterna kiselina; -[4-(2-ciklopentilamino-piridin-3-il)-2-fluoro-fenilsulfanil]-buterna kiselina; -[2-fluoro-4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-buterna kiselina;[0193] -[4-(2-cyclopropylmethoxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid; -[2,6-difluoro-4-(2-propylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-butyric acid; -[4-(6-cyclobutylsulfanyl-pyridin-2-yl)-2-fluoro-phenylsulfanyl]-butyric acid; -[4-(2-cyclopentylamino-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric acid; -[2-fluoro-4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-butyric acid;

[0194] -[4-(2-ciklobutoksi-piridin-3-il)-2-fluoro-fenilsulfanil]-buterna kiselina;[0194] -[4-(2-cyclobutoxy-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric acid;

[0195] -[2-fluoro-4-(2-pirolidin-1-il-piridin-3-il)-fenilsulfanil]-buterna kiselina;[0195] -[2-fluoro-4-(2-pyrrolidin-1-yl-pyridin-3-yl)-phenylsulfanyl]-butyric acid;

[0196] -[2-fluoro-4-(2-izopropilamino-piridin-3-il)-fenilsulfanil]-buterna kiselina;[0196] -[2-fluoro-4-(2-isopropylamino-pyridin-3-yl)-phenylsulfanyl]-butyric acid;

[0197] -(2'-ciklopentilamino-3,5'-difluoro-bifenil-4-ilsulfanil)-buterna kiselina;[0197] -(2'-cyclopentylamino-3,5'-difluoro-biphenyl-4-ylsulfanyl)-butyric acid;

[0198] -(2'-ciklopentilamino-5'-fluoro-bifenil-4-ilsulfanil)-buterna kiselina;[0198] -(2'-cyclopentylamino-5'-fluoro-biphenyl-4-ylsulfanyl)-butyric acid;

[0199] -(2'-ciklopentiloksi-5'-metil-bifenil-4-ilsulfanil)-buterna kiselina;[0199] -(2'-cyclopentyloxy-5'-methyl-biphenyl-4-ylsulfanyl)-butyric acid;

[0200] -(2'-ciklopentiloksi-4'-metoksi-bifenil-4-ilsulfanil)-buterna kiselina;[0200] -(2'-cyclopentyloxy-4'-methoxy-biphenyl-4-ylsulfanyl)-butyric acid;

[0201] -(2'-ciklopentiloksi-5'-fluoro-bifenil-4-ilsulfanil)-buterna kiselina;[0201] -(2'-cyclopentyloxy-5'-fluoro-biphenyl-4-ylsulfanyl)-butyric acid;

[0202] -(2'-ciklopentiloksi-3,5'-difluoro-bifenil-4-ilsulfanil)-buterna kiselina;[0202] -(2'-cyclopentyloxy-3,5'-difluoro-biphenyl-4-ylsulfanyl)-butyric acid;

[0203] -[4-(2-ciklopentiloksi-5-metil-piridin-3-il)-fenilsulfanil]-buterna kiselina;[0203] -[4-(2-cyclopentyloxy-5-methyl-pyridin-3-yl)-phenylsulfanyl]-butyric acid;

[0204] -(2'-ciklopentiloksi-3,5,5'-trifluoro-bifenil-4-ilsulfanil)-buterna kiselina;[0204] -(2'-cyclopentyloxy-3,5,5'-trifluoro-biphenyl-4-ylsulfanyl)-butyric acid;

[0205] -(2'-ciklopentiloksi-3-fluoro-4'-metoksi-bifenil-4-ilsulfanil)-buterna kiselina; -(2'-ciklopentiloksi-3,5-difluoro-4'-metoksi-bifenil-4-ilsulfanil)-buterna kiselina; -(3-fluoro-2'-izopropoksi-4'-metoksi-bifenil-4-ilsulfanil)-buterna kiselina;[0205] -(2'-cyclopentyloxy-3-fluoro-4'-methoxy-biphenyl-4-ylsulfanyl)-butyric acid; -(2'-cyclopentyloxy-3,5-difluoro-4'-methoxy-biphenyl-4-ylsulfanyl)-butyric acid; -(3-fluoro-2'-isopropoxy-4'-methoxy-biphenyl-4-ylsulfanyl)-butyric acid;

[0206] -[4-(2-ciklopentiloksi-5-metil-piridin-3-il)-2-fluoro-fenilsulfanil]-buterna kiselina; -[2-fluoro-4-(2-izopropoksi-5-metil-piridin-3-il)-fenilsulfanil]-buterna kiselina; -(3,5'-difluoro-2'-izopropoksi-bifenil-4-ilsulfanil)-buterna kiselina;[0206] -[4-(2-cyclopentyloxy-5-methyl-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric acid; -[2-fluoro-4-(2-isopropoxy-5-methyl-pyridin-3-yl)-phenylsulfanyl]-butyric acid; -(3,5'-difluoro-2'-isopropoxy-biphenyl-4-ylsulfanyl)-butyric acid;

[0207] -[4-(2-ciklopentiloksi-6-metil-piridin-3-il)-2-fluoro-fenilsulfanil]-buterna kiselina; -(3,3'-difluoro-2'-izopropoksi-5'-metil-bifenil-4-ilsulfanil)-buterna kiselina; -(3,3'-difluoro-5'-metil-2'-propoksi-bifenil-4-ilsulfanil)-buterna kiselina;[0207] -[4-(2-cyclopentyloxy-6-methyl-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric acid; -(3,3'-difluoro-2'-isopropoxy-5'-methyl-biphenyl-4-ylsulfanyl)-butyric acid; -(3,3'-difluoro-5'-methyl-2'-propoxy-biphenyl-4-ylsulfanyl)-butyric acid;

[0208] -(3-fluoro-2',4'-dipropoksi-bifenil-4-ilsulfanil)-buterna kiselina;[0208] -(3-fluoro-2',4'-dipropoxy-biphenyl-4-ylsulfanyl)-butyric acid;

[0209] -(6'-ciklopentiloksi-3,2'-difluoro-3'-metil-bifenil-4-ilsulfanil)-buterna kiselina; 4-(2'-ciklopentiloksi-3,3'-difluoro-bifenil-4-ilsulfanil)-buterna kiselina;[0209] -(6'-cyclopentyloxy-3,2'-difluoro-3'-methyl-biphenyl-4-ylsulfanyl)-butyric acid; 4-(2'-cyclopentyloxy-3,3'-difluoro-biphenyl-4-ylsulfanyl)-butyric acid;

[0210] 4-(2'-ciklopentiloksi-3,3'-difluoro-5'-metil-bifenil-4-ilsulfanil)-buterna kiselina;[0210] 4-(2'-cyclopentyloxy-3,3'-difluoro-5'-methyl-biphenyl-4-ylsulfanyl)-butyric acid;

[0211] 5-[4-(2-ciklobutilmetoksi-piridin-3-il)-2,6-difluoro-fenoksi]-valerijanska kiselina;[0211] 5-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-valeric acid;

[0212] 5-[4-(2-ciklopropoksi-piridin-3-il)-2,6-difluoro-fenoksi]-valerijanska kiselina;[0212] 5-[4-(2-cyclopropoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-valeric acid;

[0213] 4-[4-(2-ciklopentiloksi-5-metil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina;[0213] 4-[4-(2-cyclopentyloxy-5-methyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid;

[0214] 4-[4-(2-ciklopentiloksi-piridin-3-il)-fenilsulfanil]-valerijanska kiselina;[0214] 4-[4-(2-cyclopentyloxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid;

[0215] 4-[4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-valerijanska kiselina;[0215] 4-[4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid;

[0216] 4-[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-valerijanska kiselina;[0216] 4-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-valeric acid;

[0217] 4-[4-(2-ciklopentilsulfanil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-valerijanska kiselina;[0217] 4-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-valeric acid;

[0218] 4-[4-[2-(2-dimetilaminoetiloksi)-3-piridil]-2,6-difluoro-fenoksi]buterna kiselina;[0218] 4-[4-[2-(2-dimethylaminoethyloxy)-3-pyridyl]-2,6-difluoro-phenoxy]butyric acid;

[0219] 4-[2,6-difluoro-4-(2-propilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina;[0219] 4-[2,6-difluoro-4-(2-propylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid;

[0220] 4-[4-(2-ciklopropilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;[0220] 4-[4-(2-cyclopropylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid;

[0221] 4-[4-(2-etilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;[0221] 4-[4-(2-ethylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid;

[0222] 4-[4-(2-butilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;[0222] 4-[4-(2-Butylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid;

[0223] 4-(2'-ciklopentilamino-bifenil-4-ilsulfanil)-buterna kiselina;[0223] 4-(2'-cyclopentylamino-biphenyl-4-ylsulfanyl)-butyric acid;

[0224] 4-[4-(2-ciklopentiloksi-5-metil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;[0224] 4-[4-(2-cyclopentyloxy-5-methyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid;

[0225] 4-[4-(6-izopropilsulfanil-2-piridil)fenoksi]buterna kiselina;[0225] 4-[4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]butyric acid;

[0226] 4-[2,6-difluoro-4-(3-fenoksifenil)fenoksi]buterna kiselina;[0226] 4-[2,6-difluoro-4-(3-phenoxyphenyl)phenoxy]butyric acid;

[0227] 4-[4-[6-[3-(dimetilamino)pirolidin-1-il]-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina;[0227] 4-[4-[6-[3-(dimethylamino)pyrrolidin-1-yl]-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid;

[0228] 5-[2,6-difluoro-4-(2-izopropoksi-piridin-3-il)-fenoksi]-valerijanska kiselina;[0228] 5-[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenoxy]-valeric acid;

[0229] 5-[4-(2-ciklobutoksi-piridin-3-il)-2,6-difluoro-fenoksi]-valerijanska kiselina;[0229] 5-[4-(2-cyclobutoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-valeric acid;

[0230] 4-[4-[2-(3,3-difluoropirolidin-1-il)-3-piridil]-2,6-difluoro-fenoksi]buterna kiselina;[0230] 4-[4-[2-(3,3-difluoropyrrolidin-1-yl)-3-pyridyl]-2,6-difluoro-phenoxy]butyric acid;

[0231] 4-[2,6-difluoro-4-[2-(4-metilpiperazin-1-il)-3-piridil]fenoksi]buterna kiselina;[0231] 4-[2,6-difluoro-4-[2-(4-methylpiperazin-1-yl)-3-pyridyl]phenoxy]butyric acid;

[0232] 4-[2,6-difluoro-4-[2-(5-metilisoksazol-3-il)oksi-3-piridil]fenoksi]buterna kiselina;[0232] 4-[2,6-difluoro-4-[2-(5-methylisoxazol-3-yl)oxy-3-pyridyl]phenoxy]butyric acid;

[0233] 4-[4-[2-[2-(aziridin-1-il)etoksi]-3-piridil]-2,6-difluoro-fenoksilbuterna kiselina;[0233] 4-[4-[2-[2-(aziridin-1-yl)ethoxy]-3-pyridyl]-2,6-difluoro-phenoxybutyric acid;

[0234] 4-[2,6-difluoro-4-[2-(furilmetoksi)-3-piridil]fenoksi]buterna kiselina;[0234] 4-[2,6-difluoro-4-[2-(furylmethoxy)-3-pyridyl]phenoxy]butyric acid;

[0235] 4-[2,6-difluoro-4-[2-(2-furilmetoksi)-3-piridil]fenoksi]buterna kiselina;[0235] 4-[2,6-difluoro-4-[2-(2-furylmethoxy)-3-pyridyl]phenoxy]butyric acid;

[0236] 4-[2,6-difluoro-4-[2-[(3-metiloksetan-3-il)metoksi]-3-piridil]fenoksi] buterna kiselina;[0236] 4-[2,6-difluoro-4-[2-[(3-methyloxetan-3-yl)methoxy]-3-pyridyl]phenoxy]butyric acid;

[0237] 4-[2,6-difluoro-4-[2-(tetrahidrofuran-3-ilmetoksi)-3-piridil]fenoksi] buterna kiselina;[0237] 4-[2,6-difluoro-4-[2-(tetrahydrofuran-3-ylmethoxy)-3-pyridyl]phenoxy]butyric acid;

[0238] 4-[2,6-difluoro-4-[2-(tetrahidrofuran-2-ilmetoksi)-3-piridil]fenoksi] buterna kiselina;[0238] 4-[2,6-difluoro-4-[2-(tetrahydrofuran-2-ylmethoxy)-3-pyridyl]phenoxy]butyric acid;

[0239] 4-[4-(2-ciklobutilmetoksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;[0239] 4-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid;

[0240] 4-[4-(2-ciklopropoksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;[0240] 4-[4-(2-cyclopropoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid;

[0241] 4-(4-{2-[3-(tert-butil-dimetil-silaniloksi)-ciklopentiloksi]-piridin-3-il}-2,6-difluoro-fenoksi)-buterna kiselina;[0241] 4-(4-{2-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyloxy]-pyridin-3-yl}-2,6-difluoro-phenoxy)-butyric acid;

[0242] 4-{2,6-difluoro-4-[2-(3-hidroksi-ciklopentiloksi)-piridin-3-il]-fenoksi}-buterna kiselina;[0242] 4-{2,6-difluoro-4-[2-(3-hydroxy-cyclopentyloxy)-pyridin-3-yl]-phenoxy}-butyric acid;

[0243] 4-[4-(2-cikloheksiloksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina; -[4-(2-ciklopentilmetoksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;[0243] 4-[4-(2-cyclohexyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid; -[4-(2-cyclopentylmethoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid;

[0244] -[2,6-difluoro-4-(2-isobutoksi-piridin-3-il)-fenoksi]-buterna kiselina;[0244] -[2,6-difluoro-4-(2-isobutoxy-pyridin-3-yl)-phenoxy]-butyric acid;

[0245] -{4-[2-(2,2-dimeti-propoksi)-piridin-3-il]-2,6-difluoro-fenoksi}-buterna kiselina;[0245] -{4-[2-(2,2-dimethyl-propoxy)-pyridin-3-yl]-2,6-difluoro-phenoxy}-butyric acid;

[0246] -[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenoksi]-valerijanska kiselina;[0246] -[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-valeric acid;

[0247] -[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]valerijanska kiselina;[0247] -[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]valeric acid;

[0248] -[4-(2-ciklopentilsulfanil-3-piridil)-2,6-difluoro-fenoksi]valerijanska kiselina;[0248] -[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]valeric acid;

[0249] -[2,6-difluoro-4-(2-izopropilsulfanil-3-piridil)fenoksi]valerijanska kiselina;[0249] -[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenoxy]valeric acid;

[0250] -[2,6-difluoro-4-(2-propilsulfanil-3-piridil)fenoksi]valerijanska kiselina;[0250] -[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)phenoxy]valeric acid;

[0251] -[2,6-difluoro-4-(6-izopropilsulfanil-2-piridil)fenoksi]valerijanska kiselina;[0251] -[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]valeric acid;

[0252] -[2,6-difluoro-4-(6-izopropoksi-2-piridil)fenoksilvalerijanska kiselina;[0252] -[2,6-difluoro-4-(6-isopropoxy-2-pyridyl)phenoxyvaleric acid;

[0253] -[4-[2-(ciklopropilmetoksi)-3-piridil]-2,6-difluoro-fenoksi]valerijanska kiselina;[0253] -[4-[2-(cyclopropylmethoxy)-3-pyridyl]-2,6-difluoro-phenoxy]valeric acid;

[0254] -[2,6-difluoro-4-(2-tetrahidrofuran-3-iloksi-3-piridil)fenoksi]valerijanska kiselina; -[2,6-difluoro-4-(2-tetrahidropiran-4-iloksi-3-piridil)fenoksi]valerijanska kiselina; -[2,6-difluoro-4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-valerijanska kiselina;[0254] -[2,6-difluoro-4-(2-tetrahydrofuran-3-yloxy-3-pyridyl)phenoxy]valeric acid; -[2,6-difluoro-4-(2-tetrahydropyran-4-yloxy-3-pyridyl)phenoxy]valeric acid; -[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid;

[0255] -[4-(2-ciklopentilsulfanil-piridin-3-il)-fenilsulfanil]-valerijanska kiselina;[0255] -[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-valeric acid;

[0256] -{2-fluoro-4-[2-(tetrahidro-piran-4-iloksi)-piridin-3-il]-fenilsulfanil}-buterna kiselina; -{2-fluoro-4-[2-(tetrahidrofuran-3-iloksi)-piridin-3-il]-fenilsulfanil}-buterna kiselina; -[4-(2-ciklobutilmetoksi-piridin-3-il)-2-fluoro-fenilsulfanil]-buterna kiselina;[0256] -{2-fluoro-4-[2-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-phenylsulfanyl}-butyric acid; -{2-fluoro-4-[2-(tetrahydrofuran-3-yloxy)-pyridin-3-yl]-phenylsulfanyl}-butyric acid; -[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric acid;

[0257] -{2,6-difluoro-4-[2-(2,2,2-trifluoro-etoksi)-piridin-3-il]-fenilsulfanil}-buterna kiselina; -[4-(2-ciklobutilmetoksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina;[0257] -{2,6-difluoro-4-[2-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-phenylsulfanyl}-butyric acid; -[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid;

[0258] -[4-(2-ciklopentilamino-piridin-3-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina;[0258] -[4-(2-cyclopentylamino-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid;

[0259] -[2,6-difluoro-4-(2-izopropilamino-piridin-3-il)-fenilsulfanil]-buterna kiselina;[0259] -[2,6-difluoro-4-(2-isopropylamino-pyridin-3-yl)-phenylsulfanyl]-butyric acid;

[0260] -{4-[2-(ciklopropilmetil-amino)-piridin-3-il]-2,6-difluoro-fenilsulfanil}-buterna kiselina; -[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-valerijanska kiselina; -[2,6-difluoro-4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-valerijanska kiselina;[0260] -{4-[2-(cyclopropylmethyl-amino)-pyridin-3-yl]-2,6-difluoro-phenylsulfanyl}-butyric acid; -[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-valeric acid; -[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid;

[0261] -[4-(2-ciklopentiloksi-piridin-3-il)-fenilsulfanil]-valerijanska kiselina;[0261] -[4-(2-cyclopentyloxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid;

[0262] -[4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-valerijanska kiselina;[0262] -[4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid;

[0263] -[4-(2-ciklopentilsulfanil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-valerijanska kiselina; -[2,6-difluoro-4-(2-propilsulfanil-piridin-3-il)-fenilsulfanil]-valerijanska kiselina;[0263] -[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-valeric acid; -[2,6-difluoro-4-(2-propylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-valeric acid;

[0264] -[4-(2-ciklopentilsulfanil-piridin-3-il)-fenilsulfanil]-valerijanska kiselina;[0264] -[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-valeric acid;

[0265] -[4-(2-ciklobutilsulfanil-piridin-3-il)-fenilsulfanil]-valerijanska kiselina;[0265] -[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-valeric acid;

[0266] -[4-(2-ciklobutilmetoksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-valerijanska kiselina; -[4-(2-ciklobutoksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-valerijanska kiselina;[0266] -[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-valeric acid; -[4-(2-cyclobutoxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-valeric acid;

[0267] -[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenoksi]-kapronska kiselina;[0267] -[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-caproic acid;

[0268] -[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenoksi]-enantna kiselina;[0268] -[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-enanoic acid;

[0269] -[2-fluoro-4-(2-izopropoksi-piridin-3-il)-fenoksi]-valerijanska kiselina;[0269] -[2-fluoro-4-(2-isopropoxy-pyridin-3-yl)-phenoxy]-valeric acid;

[0270] 5-[4-(2-ciklopentilsulfanil-piridin-3-il)-2-fluoro-fenoksi]-valerijanska kiselina;[0270] 5-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2-fluoro-phenoxy]-valeric acid;

[0271] 5-[4-(2-ciklobutilsulfanil-piridin-3-il)-2-fluoro-fenoksi]-valerijanska kiselina;[0271] 5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2-fluoro-phenoxy]-valeric acid;

[0272] 5-[4-(2-ciklopentiloksi-piridin-3-il)-2-fluoro-fenoksi]-valerijanska kiselina;[0272] 5-[4-(2-cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenoxy]-valeric acid;

[0273] 4-[2,6-difluoro-4-(2-metoksi-piridin-3-il)-fenoksi]-buterna kiselina;[0273] 4-[2,6-difluoro-4-(2-methoxy-pyridin-3-yl)-phenoxy]-butyric acid;

[0274] 4-[4-(2-aliloksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;[0274] 4-[4-(2-allyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid;

[0275] 4-[4-(2-but-2-iniloksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;[0275] 4-[4-(2-but-2-ynyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid;

[0276] 6-[4-[2-(ciklobutoksi)-3-piridil]-2,6-difluoro-fenoksi]kapronska kiselina;[0276] 6-[4-[2-(cyclobutoxy)-3-pyridyl]-2,6-difluoro-phenoxy]caproic acid;

[0277] 6-[4-[2-(ciklobutilmetoksi)-3-piridil]-2,6-difluoro-fenoksi]kapronska kiselina;[0277] 6-[4-[2-(cyclobutylmethoxy)-3-pyridyl]-2,6-difluoro-phenoxy]caproic acid;

[0278] 6-[4-[2-(ciklopropilmetoksi)-3-piridil]-2,6-difluoro-fenoksi]kapronska kiselina;[0278] 6-[4-[2-(cyclopropylmethoxy)-3-pyridyl]-2,6-difluoro-phenoxy]caproic acid;

[0279] 6-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]kapronska kiselina;[0279] 6-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]caproic acid;

[0280] 6-[4-(2-ciklopentilsulfanil-3-piridil)-2,6-difluoro-fenoksi]kapronska kiselina;[0280] 6-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]caproic acid;

[0281] 6-[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-kapronska kiselina;[0281] 6-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-caproic acid;

[0282] 6-[4-(2-ciklopentilsulfanil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-kapronska kiselina;[0282] 6-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-caproic acid;

[0283] 6-[4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-kapronska kiselina; i[0283] 6-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-caproic acid; and

[0284] 6-[2,6-difluoro-4-(2-propilsulfanil-piridin-3-il)-fenilsulfanil]-kapronska kiselina.[0284] 6-[2,6-difluoro-4-(2-propylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-caproic acid.

[0285] Izrazi i skraćenice koji se ovde koriste zadržavaju svoja originalna značenja ukoliko nije drugačije naznačeno.[0285] Terms and abbreviations used herein retain their original meanings unless otherwise indicated.

[0286] Ovaj pronalazak takođe obezbeđuje postupak za pripremu ovih jedinjenja. U nastavku teksta, postupak za pripremu jedinjenja formule 1 je objašnjen na osnovu primera reakcija radi ilustrovanja ovog pronalaska. Međutim, stručnjak bi mogao da pripremi jedinjenje formule 1 primenom različitih postupaka na osnovu strukture formule 1. To znači da, jedinjenja formule 1 mogu da budu pripremljena primenom postupaka otkrivenih u prethodnom stanju tehnike. Shodno tome, postupak za pripremu jedinjenja formule 1 nije ograničen na sledeće postupke.[0286] The present invention also provides a process for the preparation of these compounds. In the following text, the procedure for the preparation of compounds of formula 1 is explained based on example reactions to illustrate the present invention. However, a person skilled in the art could prepare a compound of formula 1 using various methods based on the structure of formula 1. That is, compounds of formula 1 can be prepared using methods disclosed in the prior art. Accordingly, the process for preparing the compound of formula 1 is not limited to the following processes.

[0287] Kao što je prikazano u reakcionoj šemi 1 u nastavku, jedinjenja formule 1 mogu da budu proizvedena C-C reakcijom kuplovanja jedinjenja 2 i jedinjenja 3 u prisustvu konvencionalnog metalnog katalizatora, i, ukoliko je neophodno, dodatne hidrolize.[0287] As shown in reaction scheme 1 below, compounds of formula 1 can be produced by the C-C coupling reaction of compound 2 and compound 3 in the presence of a conventional metal catalyst, and, if necessary, additional hydrolysis.

[0288] [0288]

[0290] Dalje, jedinjenja formule 1 mogu da budu proizvedena reakcijom kuplovanja jedinjenja 4 i jedinjenja 5, jedinjenja 6 ili jedinjenja 7 u prisustvu konvencionalne baze ili reagenasa kuplovanja i, ukoliko je neophodno, dodatne hidrolize, kao što je prikazano u reakcionoj šemi 2 u nastavku. U reakcionoj šemi 2, Z-R<7>i J jedinjenja 4 i 7 nezavisno predstavljaju halogen, OH, SH ili O-alkil. Kada Z-R<7>predstavlja O-alkil, pretvoren je u OH reakcijom dealkilacije pre podvrgavanja reakciji kuplovanja.[0290] Furthermore, compounds of formula 1 can be produced by the coupling reaction of compound 4 and compound 5, compound 6 or compound 7 in the presence of a conventional base or coupling reagent and, if necessary, additional hydrolysis, as shown in reaction scheme 2 below. In reaction scheme 2, Z-R<7> and J of compounds 4 and 7 independently represent halogen, OH, SH or O-alkyl. When Z-R<7>represents O-alkyl, it is converted to OH by a dealkylation reaction before undergoing the coupling reaction.

[0292] [Reakciona šema 2][0292] [Reaction Scheme 2]

[0295] [0295]

[0298] Jedinjenja formule 1 sa različitim supstituentima takođe mogu da budu proizvedena nizom reakcionih faza, kako je prikazano u reakcionoj šemi 3 u nastavku. Specifično, jedinjenja formule I mogu biti redukovana u jedinjenje 1-1 upotrebom konvencionalnih redukcionih sredstava, a jedinjenje 1-1 može biti oksidovano u aldehidno jedinjenja (jedinjenje 1-2) upotrebom oksidacionih sredstava.[0298] Compounds of formula 1 with different substituents can also be produced by a series of reaction steps, as shown in reaction scheme 3 below. Specifically, compounds of formula I can be reduced to compound 1-1 using conventional reducing agents, and compound 1-1 can be oxidized to aldehyde compounds (compound 1-2) using oxidizing agents.

[0299] Jedinjenje 1-3 može da bude proizvedeno upotrebom konvencionalne reakcije olefinacije kao što je HWE (Horner-Wadsworth-Emmons) reakcija. Jedinjenje 1-3 može redukcijom i hidrolizom biti pretvoreno u jedinjenja formule I različitih supstituenata.[0299] Compound 1-3 can be produced using a conventional olefination reaction such as the HWE (Horner-Wadsworth-Emmons) reaction. Compound 1-3 can be converted into compounds of formula I with different substituents by reduction and hydrolysis.

[0302] [0302]

[0305] Jedinjenja formule 1 mogu da budu proizvedena reagovanjem jedinjenja 8 supstituisanog J radikalom sa jedinjenjem 9 ili jedinjenjem 10 u prisustvu konvencionalne baze, metalnih katalizatora ili reagenasa kuplovanja, kao što je prikazano u reakcionoj šemi 4 u nastavku. U reakcionoj šemi 4, J i Y nezavisno predstavljaju halogen, OH, SH ili NH<2>. Kada J predstavlja amin, "reakcija redukcione aminacije" može da bude izvedena između jedinjenja 8 i jedinjenja 11.[0305] Compounds of formula 1 can be produced by reacting J radical-substituted compound 8 with compound 9 or compound 10 in the presence of a conventional base, metal catalysts or coupling reagents, as shown in reaction scheme 4 below. In reaction scheme 4, J and Y independently represent halogen, OH, SH or NH<2>. When J represents an amine, a "reductive amination reaction" can be performed between compound 8 and compound 11.

[0306] [0306]

[0309] U gore navedenoj reakcionoj šemi 1, jedinjenje 3 može da bude proizvedeno reakcijom kuplovanja jedinjenja 12 i jedinjenja 5, jedinjenja 6 ili jedinjenja 7 u prisustvu konvencionalne baze ili reagenasa kuplovanja, kao što je prikazano u reakcionoj šemi 5 u nastavku. U reakcionoj šemi 5, J i Z-R<7>su onakvi kako su definisani u gore navedenoj reakcionoj šemi 2.[0309] In the above reaction scheme 1, compound 3 can be produced by the coupling reaction of compound 12 and compound 5, compound 6 or compound 7 in the presence of a conventional base or coupling reagent, as shown in reaction scheme 5 below. In reaction scheme 5, J and Z-R<7> are as defined in reaction scheme 2 above.

[0311] [Reakciona šema 5][0311] [Reaction Scheme 5]

[0312] U gornjoj reakcionoj šemi 2, Jedinjenje 4 može da bude proizvedeno reakcijom kuplovanja Jedinjenja 2 i Jedinjenja 12 u prisustvu konvencionalnih reagenasa kuplovanja kako što su metalni katalizatori, kao što je prikazano u reakcionoj šemi u nastavku 6.[0312] In reaction scheme 2 above, Compound 4 can be produced by the coupling reaction of Compound 2 and Compound 12 in the presence of conventional coupling reagents such as metal catalysts, as shown in reaction scheme 6 below.

[0313] U gornjim reakcionim šemama 1 do 6,[0313] In the above reaction schemes 1 to 6,

[0314] X predstavlja halogen, bornu kiselinu ili -OSO<2>CF<3>,[0314] X represents halogen, boric acid or -OSO<2>CF<3>,

[0315] Y predstavlja bornu kiselinu, halogen ili estar borne kiseline, i[0315] Y represents boric acid, halogen or boric acid ester, and

[0316] A, B, D, E, G, R<1>, R<2>, R<3>, R<4>, R<7>, m, n i p su onakvi kako su opisani u definiciji jedinjenja formule 1.[0316] A, B, D, E, G, R<1>, R<2>, R<3>, R<4>, R<7>, m, n and p are as described in the definition of compounds of formula 1.

[0317] U gornjoj reakciji, tranzicioni metal kao što je paladijum (Pd) može da se koristi kao konvencionalni metalni katalizator. Gornje reakcije mogu biti izvedene u konvencionalnim rastvaračima koji nemaju neželjeni efekat na reakcije. Poželjni rastvarači uključuju, ali bez ograničenja na, dimetilformamid, dimetilacetamid, tetrahidrofuran, acetonitril, metanol, etanol, voda, 1,2-dihloroetan, dimetilsulfoksid, etiletar, metil tert-butiletar, metilenhlorid, hloroform i njihove mešavine.[0317] In the above reaction, a transition metal such as palladium (Pd) can be used as a conventional metal catalyst. The above reactions can be carried out in conventional solvents which have no adverse effect on the reactions. Preferred solvents include, but are not limited to, dimethylformamide, dimethylacetamide, tetrahydrofuran, acetonitrile, methanol, ethanol, water, 1,2-dichloroethane, dimethyl sulfoxide, ethyl ether, methyl tert-butyl ether, methylene chloride, chloroform, and mixtures thereof.

[0318] U gornjim reakcijama, neobjašnjena jedinjenja su poznata jedinjenja ili jedinjenja koja se lako dobijaju iz poznatih jedinjenja poznatim ili sličnim postupcima.[0318] In the above reactions, the unexplained compounds are known compounds or compounds easily obtained from known compounds by known or similar methods.

[0319] Jedinjenja formule 1 dobijena primenom gornjih postupaka mogu biti razdvojena ili prečišćena od reakcionih proizvoda konvencionalnim postupcima kao što je rekristalizacija, jonosfereza, hromatografija na koloni sa silika gelom ili hromatografija razmene jona.[0319] Compounds of formula 1 obtained using the above procedures can be separated or purified from the reaction products by conventional methods such as recrystallization, ionospheresis, silica gel column chromatography or ion exchange chromatography.

[0320] Kako je gore opisano, jedinjenja prema ovom pronalasku, polazni materijali ili intermedijeri za njihovu pripremu mogu biti pripremljeni primenom različitih postupaka.[0320] As described above, the compounds according to the present invention, starting materials or intermediates for their preparation can be prepared by applying different procedures.

[0321] Jedinjenja prema ovom pronalasku imaju efekat GPR120 agonista. Shodno tome, ovaj pronalazak obezbeđuje farmaceutsku kompoziciju kao GPR120 agoniste koja obuhvata jedinjenja prema pronalasku i, njihove farmaceutski prihvatljive soli kao aktivnu komponentu. Različite vrste prolekova, koje su pretvorene u jedinjenja formule I in vivo, su takođe u razmatranju.[0321] The compounds according to the present invention have a GPR120 agonist effect. Accordingly, the present invention provides a pharmaceutical composition as a GPR120 agonist comprising the compounds of the invention and their pharmaceutically acceptable salts as an active component. Various types of prodrugs, which are converted to compounds of formula I in vivo, are also under consideration.

[0322] Primeri bolesti koje mogu biti sprečene ili lečene farmaceutskom kompozicijom prema ovom pronalasku kao GPR120 agonisti uključuju, ali bez ograničenja na, metaboličke poremećaje kao što je dijabetes, komplikacije dijabetesa, gojaznost, nealkoholna masna jetra, steatohepatitis, osteoporoza i zapaljenje.[0322] Examples of diseases that can be prevented or treated by the pharmaceutical composition of the present invention as GPR120 agonists include, but are not limited to, metabolic disorders such as diabetes, complications of diabetes, obesity, non-alcoholic fatty liver disease, steatohepatitis, osteoporosis and inflammation.

[0323] Pored toga, ovaj pronalazak obezbeđuje postupak za pripremu kompozicije za sprečavanje ili lečenje metaboličkih poremećaja kao što su dijabetes, komplikacija dijabetesa, gojaznost, nealkoholna masna jetra, steatohepatitis, osteoporoza ili zapaljenje koji obuhvata fazu mešanja jedinjenje prema pronalasku, njegovu farmaceutski prihvatljivu so kao aktivnu komponentu i farmaceutski prihvatljiv nosač.[0323] In addition, this invention provides a method for preparing a composition for preventing or treating metabolic disorders such as diabetes, complications of diabetes, obesity, non-alcoholic fatty liver disease, steatohepatitis, osteoporosis or inflammation, which includes the step of mixing a compound according to the invention, its pharmaceutically acceptable salt as an active component and a pharmaceutically acceptable carrier.

[0324] Prema ovom pronalasku, "farmaceutska kompozicija" ili "kompozicija za snižavanje nivoa glukoze u krvi" može da uključi druge komponente kao što su nosači, razblaživači, ekscipijensi, itd., pored aktivne komponente ovog pronalaska. Shodno tome, farmaceutska kompozicija može da uključi farmaceutski prihvatljive nosače, razblaživače, ekscipijense ili njihove kombinacije po potrebi. Farmaceutska kompozicija olakšava primenu jedinjenja u telo. Različiti postupci za primenu jedinjenja uključuju, ali bez ograničenja na, oralnu, primenu putem injekcije, aerosoli, parenteralnu i lokalnu primenu.[0324] According to the present invention, the "pharmaceutical composition" or "blood glucose lowering composition" may include other components such as carriers, diluents, excipients, etc., in addition to the active component of the present invention. Accordingly, the pharmaceutical composition may include pharmaceutically acceptable carriers, diluents, excipients, or combinations thereof as appropriate. The pharmaceutical composition facilitates the administration of the compound into the body. Various methods of administering the compounds include, but are not limited to, oral, injection, aerosol, parenteral, and topical administration.

[0325] Ovde, "nosači" označavaju jedinjenja koja olakšavaju dodavanje jedinjenja u ćeliju ili tkivo. Na primer, dimetilsulfoksid (DMSO) predstavlja konvencionalni nosač koji olakšava primenu mnogih organskih jedinjenja u žive ćelije ili tkiva.[0325] Here, "carriers" refer to compounds that facilitate the addition of the compound to a cell or tissue. For example, dimethylsulfoxide (DMSO) is a conventional carrier that facilitates the administration of many organic compounds into living cells or tissues.

[0326] Ovde, "razblaživači" označavaju jedinjenja koja ne samo da stabilizuju biološki aktivan oblik već su razblažena u rastvaraču koji rastvara jedinjenja. Rastvorene soli u puferu se koriste kao razblaživači u ovoj oblasti. Pufer koji se konvencionalno koristi je fosfatom puferisan slani rastvor koji imitira oblik soli u telesnoj tečnosti. Budući da puferisan rastvor može da kontroliše pH rastvor pri niskoj koncentraciji, puferisani razblaživači teško da modifikuju biološku aktivnost jedinjenja.[0326] Here, "diluents" mean compounds that not only stabilize the biologically active form but are diluted in a solvent that dissolves the compounds. Dissolved salts in the buffer are used as diluents in this area. The buffer conventionally used is a phosphate-buffered saline solution that mimics the form of salt in body fluid. Since the buffered solution can control the pH of the solution at low concentration, buffered diluents hardly modify the biological activity of the compound.

[0327] Ovde, "farmaceutski prihvatljiv" znači da takvo svojstvo ne narušava biološku aktivnost i fizičku aktivnost jedinjenja.[0327] Here, "pharmaceutically acceptable" means that such property does not impair the biological activity and physical activity of the compound.

[0328] Jedinjenja prema ovom pronalasku mogu biti formulisana kao različiti farmaceutski primenjeni dozni oblici. U pripremi farmaceutske kompozicije ovog pronalaska, specifično aktivna komponenta, jedinjenje prema ovom pronalasku je mešano sa farmaceutski prihvatljivim nosačima imajući u vidu dozni oblik koji se priprema. Na primer, farmaceutska kompozicija ovog pronalaska može biti formulisana kao injekcije, oralni preparati i njima slični, po potrebi.[0328] The compounds of the present invention can be formulated as various pharmaceutically administered dosage forms. In the preparation of the pharmaceutical composition of the present invention, the specifically active component, the compound according to the present invention is mixed with pharmaceutically acceptable carriers bearing in mind the dosage form being prepared. For example, the pharmaceutical composition of the present invention may be formulated as injections, oral preparations, and the like, as appropriate.

[0329] Jedinjenja prema pronalasku mogu biti formulisana primenom konvencionalnih postupaka upotrebom poznatih farmaceutskih nosača i ekscipijenasa, i stavljena u jedinična ili višejedinična pakovanja. Formulacije mogu biti rastvor, suspenzija ili emulzija u ulju ili vodeni rastvarač i uključuju konvencionalna sredstva za dispergovanje, sredstva za suspendovanje ili sredstva za stabilizovanje. Pored toga, jedinjenja mogu biti, na primer, oblik suvog praška koji je rastvoren u sterilnoj vodi bez pirogena pre upotrebe. Jedinjenja ovog pronalaska mogu biti formulisana u supozitorije upotrebom konvencionalne baze supozitorije kao što je kakao maslac ili drugi gliceridi. Čvrsti oblici za oralnu primena uključuju kapsule, tablete, pilule, praškove i granule. Kapsule i tablete su poželjne. Tablete i pilule su poželjno enterički obložene. Čvrsti oblici su proizvedeni mešanjem jedinjenja ovog pronalaska sa najmanje jednim nosačem izabranim između inertnih razblaživača kao što je saharoza, laktoza ili skrob, lubrikanti kao što su magnezijumstearate, sredstva za raspadanje, sredstva za vezivanje i njima slični.[0329] The compounds according to the invention can be formulated using conventional methods using known pharmaceutical carriers and excipients, and placed in unit or multi-unit packages. The formulations may be a solution, suspension or emulsion in oil or aqueous solvent and include conventional dispersing agents, suspending agents or stabilizing agents. In addition, the compounds may be, for example, in dry powder form that is dissolved in sterile, pyrogen-free water prior to use. The compounds of the present invention may be formulated into suppositories using a conventional suppository base such as cocoa butter or other glycerides. Solid forms for oral administration include capsules, tablets, pills, powders and granules. Capsules and tablets are preferred. Tablets and pills are preferably enteric coated. Solid forms are produced by mixing the compounds of this invention with at least one carrier selected from inert diluents such as sucrose, lactose or starch, lubricants such as magnesium stearate, disintegrants, binders and the like.

[0330] Jedinjenja prema ovom pronalasku mogu biti primenjena u kombinaciji sa drugim lekovima-na primer, drugim antidijabeticima po potrebi.[0330] The compounds of the present invention may be administered in combination with other drugs—for example, other antidiabetic agents as needed.

[0331] Doza jedinjenja prema ovom pronalasku je određena u skladu sa receptom lekara koji u obzir uzima telesnu masu pacijenta, starost i stanje bolesti. Uobičajena doza za odrasle je u opsegu od oko 0.3 do 500 mg dnevno prema učestalosti i intenzitetu primene. Uobičajena dnevna doza intramuskularne ili intravenske primene za odrasle je u opsegu od oko 1 do 300 mg dnevno koja može biti primenjena u podeljenim jediničnim dozama. Nekim pacijentima je potrebna veća dnevna doza.[0331] The dose of the compound according to the present invention is determined according to the doctor's prescription that takes into account the patient's body weight, age and disease state. The usual dose for adults is in the range of about 0.3 to 500 mg per day according to the frequency and intensity of application. The usual daily dose for intramuscular or intravenous administration for adults is in the range of about 1 to 300 mg per day which may be administered in divided unit doses. Some patients need a higher daily dose.

[0332] Ovaj pronalazak takođe obezbeđuje jedinjenja za upotrebu u postupku za sprečavanje ili lečenje bolesti upotrebom efektivne količine jedinjenja prema zahtevu 1 ili njegove farmaceutski prihvatljive soli kao aktivne komponente GPR120 agonista. Reprezentativne bolesti koje bi trebalo lečiti GPR120 agonistima uključuju, ali bez ograničenja na, metaboličke poremećaje kao što su gore pomenuti dijabetes, komplikacije dijabetesa, gojaznost, nealkoholna masna jetra, steatohepatitis, osteoporoza, zapaljenje i njima slične. Ovde se izraz "lečenje" koristi da označi zadržavanje, odlaganje ili poboljšanje napretka bolesti kod subjekta koji ispoljava simptome bolesti. Izraz "sprečavanje" se koristi da označi odvraćanje, odlaganje ili poboljšanje znaka bolseti kod subjekta kod kog postoji rizik od izlaganja simptomima bolesti, čak i ako on ili ona ne ispoljavaju simptome.[0332] The present invention also provides compounds for use in a method for preventing or treating a disease using an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active component of a GPR120 agonist. Representative diseases that should be treated with GPR120 agonists include, but are not limited to, metabolic disorders such as the aforementioned diabetes, complications of diabetes, obesity, non-alcoholic fatty liver disease, steatohepatitis, osteoporosis, inflammation and the like. As used herein, the term "treating" is used to mean the arrest, delay, or amelioration of disease progression in a subject exhibiting symptoms of the disease. The term "prevention" is used to denote the averting, delaying, or amelioration of a sign of illness in a subject at risk of exposure to symptoms of the disease, even if he or she does not exhibit symptoms.

[0334] Poželjni efekti pronalaska[0334] Desirable effects of the invention

[0335] Biarilni derivati prema ovom pronalasku promovišu formiranje GLP-1 u gastrointestinalnom traktu i poboljšavaju otpornost insulina u jetri ili mišićima usled antizapaljenske aktivnosti u makrofagovima, lipocitima, itd., i shodno tome se mogu efektivno koristiti za sprečavanje ili lečenje metaboličkih poremećaja kao što su dijabetes, komplikacije dijabetesa, gojaznost, nealkoholna masna jetra, steatohepatitis, osteoporoza ili zapaljenje.[0335] Biaryl derivatives according to the present invention promote the formation of GLP-1 in the gastrointestinal tract and improve insulin resistance in the liver or muscles due to anti-inflammatory activity in macrophages, lipocytes, etc., and accordingly can be effectively used to prevent or treat metabolic disorders such as diabetes, complications of diabetes, obesity, non-alcoholic fatty liver, steatohepatitis, osteoporosis or inflammation.

[0337] Način za izum[0337] Method for the invention

[0338] Ovaj pronalazak je detaljnije objašnjen kroz primere u nastavku. Međutim, ovi primeri samo ilustruju ovaj pronalazak, i ne ograničavaju njegovu oblast.[0338] The present invention is explained in more detail through the examples below. However, these examples only illustrate the present invention, and do not limit its scope.

[0339] U nastavku, M označava molarnu koncentraciju a N označava normalnu koncentraciju. Dalje, skraćenice koje se koriste u pripremama i primerima su sledeće:[0339] In the following, M denotes molar concentration and N denotes normal concentration. Further, the abbreviations used in the preparations and examples are as follows:

[0340] BBr<3>: bortribromid[0340] BBr<3>: boron tribromide

[0341] BINAP: 2,2'-bis(difenilfosfino)-1,1'-binaftil[0341] BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

[0342] Br<2>: bromin[0342] Br<2>: bromine

[0343] CH<3>CN: acetonitril[0343] CH<3>CN: acetonitrile

[0344] Cs<2>CO<3>: cezijumkarbonat[0344] Cs<2>CO<3>: cesium carbonate

[0345] DCM: dihlorometan[0345] DCM: dichloromethane

[0346] DMF: N,N-dimetilformamid[0346] DMF: N,N-dimethylformamide

[0347] DMSO: dimetilsulfoksid[0347] DMSO: dimethylsulfoxide

[0348] DPPF: 1,1'-bis(difenilfosfino)ferocen[0348] DPPF: 1,1'-bis(diphenylphosphino)ferrocene

[0349] EtOAc: etilacetat[0349] EtOAc: ethyl acetate

[0350] EtOH: etanol[0350] EtOH: ethanol

[0351] Et<2>O: dietil etar[0351] Et<2>O: diethyl ether

[0352] HCl: hlorovodonična kiselina[0352] HCl: Hydrochloric acid

[0353] Hex: n-heksan[0353] Hex: n-hexane

[0354] K<2>CO<3>: kalijumkarbonat[0354] K<2>CO<3>: potassium carbonate

[0355] LAH: litijumaluminijumhidrid[0355] LAH: lithium aluminum hydride

[0356] MeOH: metanol[0356] MeOH: methanol

[0357] MgSO<4>: magnezijumsulfat[0357] MgSO<4>: magnesium sulfate

[0358] NaBH<4>: natrijumborohidrid[0358] NaBH<4>: sodium borohydride

[0359] NaCl: natrijumhlorid[0359] NaCl: sodium chloride

[0360] Na<2>CO<3>: natrijumkarbonat[0360] Na<2>CO<3>: sodium carbonate

[0361] NaH: natrijumhidrid[0361] NaH: sodium hydride

[0362] NaOH: natrijumhidroksid[0362] NaOH: sodium hydroxide

[0363] NBS: N-bromosukcinimid[0363] NBS: N-bromosuccinimide

[0364] Pd/C: paladijum/ugljenik[0364] Pd/C: palladium/carbon

[0365] PdCl<2>(dppf)-DCM: 1,1'-bis(difenilfosfino)ferocen-paladijum(II) dihlorid dihlorometan PdCl<2>(PPh<3>)<2>: bis(trifenilfosfin)paladijum(II) dihlorid[0365] PdCl<2>(dppf)-DCM: 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane PdCl<2>(PPh<3>)<2>: bis(triphenylphosphine)palladium(II) dichloride

[0366] Pd<2>(dba)<3>: tris(dibenzilidenaceton)dipaladijum(0)[0366] Pd<2>(dba)<3>: tris(dibenzylideneacetone)dipalladium(0)

[0367] Pd(PPh<3>)<4>: tetrakis(trifenilfosfin)paladijum(0)[0367] Pd(PPh<3>)<4>: tetrakis(triphenylphosphine)palladium(0)

[0368] SOCl<2>: tionilhlorid[0368] SOCl<2>: thionyl chloride

[0369] SPhos: 2-dicikloheksilfosfino-2',6'-dimetoksibifenil[0369] SPhos: 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl

[0370] TBAF:tetrabutilamonijakfluoridhidrat[0370] TBAF: tetrabutylammonium fluoride hydrate

[0371] TEA: trietilamin[0371] TEA: triethylamine

[0372] TFA: trifluorosirćetna kiselina[0372] TFA: trifluoroacetic acid

[0373] THF: tetrahidrofuran[0373] THF: tetrahydrofuran

[0374] XPhos: 2-dicikloheksilfosfino-2',4' ,6'-triizopropilbifenil[0374] XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0376] Primer pripreme 1: etil estar 4-[4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline Faza A: 4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenol[0376] Preparation example 1: 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester Phase A: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

[0377] 4-hlorofenol (2 g, 15.5 mmol), bis(pinakolato)dibor (5.92 g, 23.3 mmol), kalijumacetat (4.58 g, 46.6 mmol) i Xphos (0.3 g, 0.62 mmol) su rastvoreni u 30 mL 1,4-dioksana, i mešavini je dodavan N<2>gas 5 minuta. Dodat je Pd<2>(dba)<3>(0.14 g, 0.15 mmol), i mešavina je mešana 1 sat na 110°C. Mešavina je filtrirana kroz Celite a zatim prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (3.4 g, 99 %).[0377] 4-Chlorophenol (2 g, 15.5 mmol), bis(pinacolato)diboron (5.92 g, 23.3 mmol), potassium acetate (4.58 g, 46.6 mmol), and Xphos (0.3 g, 0.62 mmol) were dissolved in 30 mL of 1,4-dioxane, and N<2 >gas was added to the mixture for 5 minutes. Pd<2>(dba)<3> (0.14 g, 0.15 mmol) was added, and the mixture was stirred for 1 hour at 110°C. The mixture was filtered through Celite and then purified by column chromatography to give the title compound (3.4 g, 99 %).

[0378] <1>H NMR (CDCl<3>) δ 7.71 (2H, d), 6.82 (2H, d), 5.00 (1H, s), 1.33 (12H, s)[0378] <1>H NMR (CDCl<3>) δ 7.71 (2H, d), 6.82 (2H, d), 5.00 (1H, s), 1.33 (12H, s)

[0380] Faza B: etil estar 4-[4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline[0380] Phase B: 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester

[0381] 4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenol dobijen iz faze A (0.32 g, 1.4 mmol) je rastvoren u 5 mL DMF-a. Dodati su K<2>CO<3>(0.39 g, 2.8 mmol) i etil estar 4-buterne kiseline (0.22 mL, 1.54 mmol), i mešavina je mešana 1 sat na 60°C. Čvrste materije su uklonjene i mešavina je prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.38 g, 82 %).[0381] The 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol obtained from phase A (0.32 g, 1.4 mmol) was dissolved in 5 mL of DMF. K<2>CO<3> (0.39 g, 2.8 mmol) and 4-butyric acid ethyl ester (0.22 mL, 1.54 mmol) were added, and the mixture was stirred for 1 hour at 60°C. The solids were removed and the mixture was purified by column chromatography to give the title compound (0.38 g, 82 %).

[0382] <1>H NMR (CDCl<3>) δ 7.73 (2H, d), 6.87 (2H, d), 4.14 (2H, q), 4.03 (2H, t), 2.51 (2H, t), 2.11 (2H, m), 1.32 (12H, s), 1.25 (3H, t)[0382] <1>H NMR (CDCl<3>) δ 7.73 (2H, d), 6.87 (2H, d), 4.14 (2H, q), 4.03 (2H, t), 2.51 (2H, t), 2.11 (2H, m), 1.32 (12H, s), 1.25 (3H, t)

[0384] Primer pripreme 2: etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiselinePreparation example 2: 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester

[0385] Faza A: 4-bromo-2.6-difluoro-fenol[0385] Phase A: 4-bromo-2,6-difluoro-phenol

[0386] 2,6-difluorofenol (1.02 g, 7.8 mmol) je rastvoren u 15 mL DMF-a, i na 0°C je dodat NBS (1.40 g, 7.84 mmol). Reakciona mešavina je mešana 24 sata na sobnoj temperaturi i koncentrovana. Dodato je 50 mL vode, i mešavina je ekstrahovana sa Et<2>O. Ekstrakt je osušen sa MgSO<4>da bi se dobilo naslovno jedinjenje (1.41 g, 86 %).[0386] 2,6-Difluorophenol (1.02 g, 7.8 mmol) was dissolved in 15 mL of DMF, and NBS (1.40 g, 7.84 mmol) was added at 0°C. The reaction mixture was stirred for 24 hours at room temperature and concentrated. 50 mL of water was added, and the mixture was extracted with Et<2>O. The extract was dried with MgSO<4> to give the title compound (1.41 g, 86 %).

[0387] <1>H NMR (CDCl<3>) δ 7.08 (2H, m), 5.42 (1H, brs)[0387] <1>H NMR (CDCl<3>) δ 7.08 (2H, m), 5.42 (1H, brs)

[0389] Faza B: 2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenol[0389] Phase B: 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

[0390] 4-bromo-2,6-difluoro-fenol dobijen iz faze A (1.414 g, 6.76 mmol), bis(pinakolato)dibor (1.8 g, 7.09 mmol), kalijumacetat (2.66 g, 27 mmol) i DPPF (0.19 g, 0.34 mmol) su rastvoreni u 23 mL 1,4-dioksana, i mešavini je dodavan N<2>gas 5 minuta. Dodat je PdCl<2>(dppf)-DCM (0.27 g, 0.34 mmol), i mešavina je mešana 3 sata na 80°C. Mešavina je filtrirana kroz Celite i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (1.366 g, 79 %).[0390] 4-bromo-2,6-difluoro-phenol obtained from phase A (1.414 g, 6.76 mmol), bis(pinacolato)diboron (1.8 g, 7.09 mmol), potassium acetate (2.66 g, 27 mmol) and DPPF (0.19 g, 0.34 mmol) were dissolved in 23 mL of 1,4-dioxane, and the mixture was added. N<2>gas for 5 minutes. PdCl<2>(dppf)-DCM (0.27 g, 0.34 mmol) was added, and the mixture was stirred for 3 hours at 80°C. The mixture was filtered through Celite and purified by column chromatography to give the title compound (1,366 g, 79 %).

[0391] <1>H NMR (CDCl<3>) δ 7.33 (2H, m), 5.25 (1H, s), 1.32 (12H, s)[0391] <1>H NMR (CDCl<3>) δ 7.33 (2H, m), 5.25 (1H, s), 1.32 (12H, s)

[0393] Faza C: etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il) fenoksi]buterne kiseline[0393] Phase C: 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester

[0394] 2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenol dobijen iz faze B (1.87 g, 7.3 mmol), Cs<2>CO<3>(4.76 g, 14.6 mmol) i etil estar 4-bromo-buterne kiseline (1.42 g, 7.3 mmol) su rastvoreni u 24 mL DMF-a. Mešavina je mešana 24 sata na sobnoj temperaturi. Čvrste materije su filtrirane, a filtrat je prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (1.66 g, 61 %).[0394] 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol obtained from phase B (1.87 g, 7.3 mmol), Cs<2>CO<3> (4.76 g, 14.6 mmol) and 4-bromo-butyric acid ethyl ester (1.42 g, 7.3 mmol) were dissolved in 24 mL. of DMF. The mixture was stirred for 24 hours at room temperature. The solids were filtered, and the filtrate was purified by column chromatography to give the title compound (1.66 g, 61 %).

[0395] <1>H NMR (CDCl<3>) δ 7.29 (2H, m), 4.21 (2H, t), 4.14 (2H, q), 2.56 (2H, t), 2.07 (2H, m), 1.32 (12H, s), 1.25 (3H, t)[0395] <1>H NMR (CDCl<3>) δ 7.29 (2H, m), 4.21 (2H, t), 4.14 (2H, q), 2.56 (2H, t), 2.07 (2H, m), 1.32 (12H, s), 1.25 (3H, t)

[0397] Primer pripreme 3: etil estra 4-[2-hloro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiselinePreparation example 3: 4-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester

[0398] Faza A: 2-hloro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenol[0398] Phase A: 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

[0399] 4-bromo-2-hlorofenol (2.0 g, 9.6 mmol), bis(pinakolato)dibor (2.81 g, 11 mmol), kalijumacetat (3.78 g, 38.5 mmol) i DPPF (0.27 g, 0.49 mmol) su rastvoreni u 32 mL 1,4-dioksana. Mešavini je dodavan N<2>gas 5 minuta. Dodat je PdCl<2>(dppf)-DCM (0.4 g, 0.49 mmol), i mešavina je mešana 3 sata pod refluksom. Mešavina je filtrirana kroz Celite i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (1.91 g, 77 %).[0399] 4-Bromo-2-chlorophenol (2.0 g, 9.6 mmol), bis(pinacolato)diboron (2.81 g, 11 mmol), potassium acetate (3.78 g, 38.5 mmol) and DPPF (0.27 g, 0.49 mmol) were dissolved in 32 mL of 1,4-dioxane. N<2>gas was added to the mixture for 5 minutes. PdCl<2>(dppf)-DCM (0.4 g, 0.49 mmol) was added, and the mixture was stirred for 3 h under reflux. The mixture was filtered through Celite and purified by column chromatography to give the title compound (1.91 g, 77 %).

[0400] <1>H NMR (CDCl<3>) δ 7.77 (1H, s), 7.62 (1H, dd), 7.00 (1H, d), 5.73 (1H, s), 1.36 (12H, s)[0400] <1>H NMR (CDCl<3>) δ 7.77 (1H, s), 7.62 (1H, dd), 7.00 (1H, d), 5.73 (1H, s), 1.36 (12H, s)

[0402] Faza B: etil estar 4-[2-hloro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline [0065] 2-hloro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenol dobijen iz faze A (0.43 g, 1.7 mmol), etil estar 4-bromo-buterne kiseline (0.25 mL, 1.7 mmol) i Cs<2>CO<3>(0.66 g, 2 mmol) su rastvoreni u 5 mL DMF-a. Reakciona mešavina je mešana 16 sati na sobnoj temperaturi. Mešavina je koncentrovana i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.47 g, 75 %).Phase B: 4-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester 4-Bromo-butyric acid (0.25 mL, 1.7 mmol) and Cs<2>CO<3> (0.66 g, 2 mmol) were dissolved in 5 mL of DMF. The reaction mixture was stirred for 16 hours at room temperature. The mixture was concentrated and purified by column chromatography to give the title compound (0.47 g, 75 %).

[0403] <1>H NMR (CDCl<3>) δ 7.79 (1H, d), 7.63 (1H, dd), 6.89 (1H, d), 4.15 (2H, t), 4.10 (2H, q), 2.56 (2H, t), 2.16 (2H, m), 1.33 (12H, s), 1.25 (3H, t)[0403] <1>H NMR (CDCl<3>) δ 7.79 (1H, d), 7.63 (1H, dd), 6.89 (1H, d), 4.15 (2H, t), 4.10 (2H, q), 2.56 (2H, t), 2.16 (2H, m), 1.33 (12H, s), 1.25 (3H, t)

[0405] Primer pripreme 4: etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiselinePreparation example 4: 4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester

[0406] Faza A: 2-fluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenol[0406] Phase A: 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

[0407] 4-bromo-2-fluorofenol (1,9 g, 9.9 mmol), bis(pinakolato)dibor (2.9 g, 11.4 mmol), kalijumacetat (3.90 g, 39.7 mmol) i DPPF (0.27 g, 0.49 mmol) su rastvoreni u 32 mL 1,4-dioksana. Mešavini je dodavan N<2>gas 5 minuta. Dodat je PdCl<2>(dppf)-DCM (0.4 g, 0.49 mmol) , i mešavina je mešana 4 sata pod refluksom. Mešavina je filtrirana kroz Celite a zatim prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (2.2 g, 93 %).[0407] 4-Bromo-2-fluorophenol (1.9 g, 9.9 mmol), bis(pinacolato)diboron (2.9 g, 11.4 mmol), potassium acetate (3.90 g, 39.7 mmol) and DPPF (0.27 g, 0.49 mmol) were dissolved in 32 mL of 1,4-dioxane. N<2>gas was added to the mixture for 5 minutes. PdCl<2>(dppf)-DCM (0.4 g, 0.49 mmol) was added, and the mixture was stirred for 4 hours under reflux. The mixture was filtered through Celite and then purified by column chromatography to give the title compound (2.2 g, 93 %).

[0408] <1>H NMR (CDCl<3>) δ 7.49 (2H, m), 6.98 (1H, t), 5.31 (1H, brs), 1.33 (12H, s)[0408] <1>H NMR (CDCl<3>) δ 7.49 (2H, m), 6.98 (1H, t), 5.31 (1H, brs), 1.33 (12H, s)

[0410] Faza B: etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline [0069] 2-fluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenol dobijen iz faze A (0.56 g, 2.3 mmol), etil estar 4-bromo-buterne kiseline (0.34 mL, 2.3 mmol) i Cs<2>CO<3>(0.92 g, 2.8 mmol) su rastvoreni u 8 mL DMF-a. Reakciona mešavina je mešana 16 sati na sobnoj temperaturi. Mešavina je koncentrovana i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.52 g, 63 %).[0410] Phase B: 4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester [0069] 2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol from phase A (0.56 g, 2.3 mmol), ethyl ester 4-Bromo-butyric acid (0.34 mL, 2.3 mmol) and Cs<2>CO<3> (0.92 g, 2.8 mmol) were dissolved in 8 mL of DMF. The reaction mixture was stirred for 16 hours at room temperature. The mixture was concentrated and purified by column chromatography to give the title compound (0.52 g, 63 %).

[0411] <1>H NMR (CDCl<3>) δ 7.49 (2H, m), 6.93 (1H, t), 4.15 (2H, t), 4.10 (2H, q), 2.53 (2H, t), 2.15 (2H, m), 1.33 (12H, s), 1.25 (3H, t)[0411] <1>H NMR (CDCl<3>) δ 7.49 (2H, m), 6.93 (1H, t), 4.15 (2H, t), 4.10 (2H, q), 2.53 (2H, t), 2.15 (2H, m), 1.33 (12H, s), 1.25 (3H, t)

[0413] Primer pripreme 5: 2-hloro-6-ciklopentilsulfanil-piridin[0413] Preparation example 5: 2-chloro-6-cyclopentylsulfanyl-pyridine

[0414] 2,6-dihloropiridin (3.08 g, 20.7 mmol) i Cs<2>CO<3>(6.8 g, 20.7 mmol) su rastvoreni u 40 mL DMF-a. Dodat je ciklopentiltiol (2.17 mL, 20.7 mmol) i mešavina je mešana 16 sati na 80°C. Čvrste materije su filtrirane i filtrat je koncentrovan da bi se dobilo naslovno jedinjenje (4.24 g, 95 %).[0414] 2,6-Dichloropyridine (3.08 g, 20.7 mmol) and Cs<2>CO<3> (6.8 g, 20.7 mmol) were dissolved in 40 mL of DMF. Cyclopentylthiol (2.17 mL, 20.7 mmol) was added and the mixture was stirred for 16 hours at 80°C. The solids were filtered and the filtrate was concentrated to give the title compound (4.24 g, 95 %).

[0415] <1>H NMR (CDCl<3>) δ 7.40 (1H, t), 7.06 (1H, d), 6.97 (1H, d), 4.01 (1H, m), 2.22 (2H, m), 1.76 (2H, m), 1.64 (4H, m)[0415] <1>H NMR (CDCl<3>) δ 7.40 (1H, t), 7.06 (1H, d), 6.97 (1H, d), 4.01 (1H, m), 2.22 (2H, m), 1.76 (2H, m), 1.64 (4H, m)

[0417] Primer pripreme 6 etil estar: 4-[2-metoksi-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline[0417] Preparation example 6 ethyl ester: 4-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid

[0418] 4-bromo-2-metoksi-fenol (0.41 g, 2.02 mmol) i etil estar 4-bromo-buterne kiseline (0.39 g, 2.02 mmol) su izreagovani na isti način kao u fazi B primera pripreme 4 da bi se dobio etil estar 4-(4-bromo-2-metoksi-fenoksi)-buterne kiseline (0.55 g, 86 %).[0418] 4-Bromo-2-methoxy-phenol (0.41 g, 2.02 mmol) and 4-bromo-butyric acid ethyl ester (0.39 g, 2.02 mmol) were reacted in the same manner as in phase B of Preparation Example 4 to give 4-(4-bromo-2-methoxy-phenoxy)-butyric acid ethyl ester (0.55 g, 86%).

[0419] Etil estar 4-(4-bromo-2-metoksi-fenoksi)-buterne kiseline (130 mg, 0.41 mmol) i bis(pinakolato)dibor (125 mg, 0.49 mmol) su izreagovani na isti način kao u fazi A primera pripreme 4 da bi se dobilo naslovno jedinjenje(80 mg, 54 %).[0419] 4-(4-Bromo-2-methoxy-phenoxy)-butyric acid ethyl ester (130 mg, 0.41 mmol) and bis(pinacolato)diboron (125 mg, 0.49 mmol) were reacted in the same manner as in Step A of Preparation Example 4 to give the title compound (80 mg, 54%).

[0420] <1>H NMR (CDCl<3>) δ 7.39(1H, d), 7.28(1H, s), 6.88(1H, d), 4.14(2H, q), 4.09(2H, t), 3.89(3H, s), 2.52(2H, t), 2.14(2H, m), 1.33(12H, s), 1.26(3H, t)[0420] <1>H NMR (CDCl<3>) δ 7.39(1H, d), 7.28(1H, s), 6.88(1H, d), 4.14(2H, q), 4.09(2H, t), 3.89(3H, s), 2.52(2H, t), 2.14(2H, m), 1.33(12H, s), 1.26(3H, t)

[0422] Primer pripreme 7: etil estar 4-[4-(2-hloro-4-piridil)-2,6-difluoro-fenoksi]buterne kiselinePreparation example 7: 4-[4-(2-chloro-4-pyridyl)-2,6-difluoro-phenoxy]butyric acid ethyl ester

[0423] 2 mL THF-a i 0.5 mL vode je dodato u etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline dobijen iz primera pripreme 2 (0.1 g, 0.27 mmol), 2-hloro-4-jodopiridina (0.078 g, 0.32 mmol) i K<2>CO<3>(0.112 g, 0.81 mmol). Mešavini je dodavan N<2>gas 5 minuta. Dodat je PdCl<2>(dppf)-DCM (0.011 g, 0.013 mmol), i mešavina je mešana 16 sati na 80°C. Dodata je voda i reakciona mešavina je ekstrahovana sa EtOAc. Ekstrakt je osušen sa MgSO<4>i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.084 g, 87 %).[0423] 2 mL of THF and 0.5 mL of water were added to 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester obtained from Preparation Example 2 (0.1 g, 0.27 mmol), 2-chloro-4-iodopyridine (0.078 g, 0.32 mmol) and K<2>CO<3> (0.112 g, 0.81 mmol). N<2>gas was added to the mixture for 5 minutes. PdCl<2>(dppf)-DCM (0.011 g, 0.013 mmol) was added, and the mixture was stirred for 16 hours at 80°C. Water was added and the reaction mixture was extracted with EtOAc. The extract was dried with MgSO4 and purified by column chromatography to give the title compound (0.084 g, 87 %).

[0424] <1>H NMR (CDCl<3>) δ 8.44 (1H, d), 7.45 (1H, d), 7.33 (1H, dd), 7.17 (2H, m), 4.26 (2H, t), 4.17 (2H, q), 2.58 (2H, t), 2.11 (2H, m), 1.27 (3H, t)[0424] <1>H NMR (CDCl<3>) δ 8.44 (1H, d), 7.45 (1H, d), 7.33 (1H, dd), 7.17 (2H, m), 4.26 (2H, t), 4.17 (2H, q), 2.58 (2H, t), 2.11 (2H, m), 1.27 (3H, t)

[0426] Primer pripreme 8: 2-hloro-6-(ciklopentoksi)piridin[0426] Preparation example 8: 2-chloro-6-(cyclopentoxy)pyridine

[0427] 6-hloro-2-piridinol (1.95 g, 15 mmol) i K<2>CO<3>(4.16 g, 30 mmol) su rastvoreni u 50 mL DMF-a. Dodat je ciklopentil bromid (1.94 mL, 18 mmol) i mešavina je mešana 24 sata na 80°C. Čvrste materije su uklonjene i filtrat je koncentrovan da bi se dobilo naslovno jedinjenje (2.92 g, 98 %).[0427] 6-chloro-2-pyridinol (1.95 g, 15 mmol) and K<2>CO<3> (4.16 g, 30 mmol) were dissolved in 50 mL of DMF. Cyclopentyl bromide (1.94 mL, 18 mmol) was added and the mixture was stirred for 24 hours at 80°C. The solids were removed and the filtrate was concentrated to give the title compound (2.92 g, 98 %).

[0428] <1>H NMR (CDCl<3>) δ 7.47 (1H, t), 6.84 (1H, d), 6.51 (1H, d), 5.38 (1H, m), 1.97 (2H, m), 1.79 (4H, m), 1.62 (2H, m)[0428] <1>H NMR (CDCl<3>) δ 7.47 (1H, t), 6.84 (1H, d), 6.51 (1H, d), 5.38 (1H, m), 1.97 (2H, m), 1.79 (4H, m), 1.62 (2H, m)

[0430] Primer pripreme 9: 1-bromo-3-(ciklopentoksi)benzen[0430] Preparation example 9: 1-bromo-3-(cyclopentoxy)benzene

[0431] 44 mL CH<3>CN je dodato u 3-bromofenol (2.31 g, 13.3 mmol) i K<2>CO<3>(1.84 g, 13.3 mmol), i mešavina je mešana 1 sat pod refluksom. Dodat je bromociklopentan (1.43 mL, 13.3 mmol), i reakciona mešavina je mešana 16 sati pod refluksom. Mešavina je filtrirana kroz Celite a zatim prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (1.5 g, 46 %).[0431] 44 mL of CH<3>CN was added to 3-bromophenol (2.31 g, 13.3 mmol) and K<2>CO<3> (1.84 g, 13.3 mmol), and the mixture was stirred for 1 hour under reflux. Bromocyclopentane (1.43 mL, 13.3 mmol) was added, and the reaction mixture was stirred for 16 h under reflux. The mixture was filtered through Celite and then purified by column chromatography to give the title compound (1.5 g, 46 %).

[0432] <1>H NMR (CDCl<3>) δ 7.11 (1H, t), 7.02 (2H, m), 6.80 (1H, dd), 4.72 (1H, m), 1.94-1.73 (6H, m), 1.62 (2H, m),[0432] <1>H NMR (CDCl<3>) δ 7.11 (1H, t), 7.02 (2H, m), 6.80 (1H, dd), 4.72 (1H, m), 1.94-1.73 (6H, m), 1.62 (2H, m),

[0434] Primer pripreme 10: 2-hloro-6-pirolidin-1-il-piridin[0434] Preparation example 10: 2-chloro-6-pyrrolidin-1-yl-pyridine

[0435] 2,6-dihloropiridin (2.08 g, 14 mmol) i pirolidin (1.0 g, 14 mmol), Cs<2>CO<3>(4.58 g, 14 mmol) su rastvoreni u 28 mL DMF-a i mešavina je mešana 16 sati na 80°C. Mešavina je filtrirana kroz Celite, koncentrovana pod smanjenim pritiskom i razblažena vodom. Mešavina je ekstrahovana sa EtOAc i ekstrakt je osušen sa MgSO<4>da bi se dobilo naslovno jedinjenje (2.31 g, 90 %).[0435] 2,6-dichloropyridine (2.08 g, 14 mmol) and pyrrolidine (1.0 g, 14 mmol), Cs<2>CO<3> (4.58 g, 14 mmol) were dissolved in 28 mL of DMF and the mixture was stirred for 16 hours at 80°C. The mixture was filtered through Celite, concentrated under reduced pressure and diluted with water. The mixture was extracted with EtOAc and the extract was dried over MgSO4 to give the title compound (2.31 g, 90 %).

[0436] <1>H NMR (CDCl<3>) δ 7.32 (1H, t), 6.49 (1H, d), 6.20 (1H, d), 3.43 (4H, m), 1.99 (4H, m)[0436] <1>H NMR (CDCl<3>) δ 7.32 (1H, t), 6.49 (1H, d), 6.20 (1H, d), 3.43 (4H, m), 1.99 (4H, m)

[0438] Primer pripreme 11: etil estar 4-[2,6-dimetil-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiselinePreparation example 11: 4-[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester

[0439] 4-bromo-2,6-dimetil-fenol (1.0 g, 4.97 mmol) i etil estar 4-bromo-buterne kiseline (0.97 g, 4.97 mmol) su izreagovani na isti način kao u fazi B primera pripreme 4 da bi se dobio etil estar 4-(4-bromo-2,6-dimetil-fenoksi)-buterne kiseline (1.4 g, 89 %).[0439] 4-bromo-2,6-dimethyl-phenol (1.0 g, 4.97 mmol) and 4-bromo-butyric acid ethyl ester (0.97 g, 4.97 mmol) were reacted in the same manner as in phase B of Preparation Example 4 to give 4-(4-bromo-2,6-dimethyl-phenoxy)-butyric acid ethyl ester (1.4 g, 89%).

[0440] Etil estar 4-(4-bromo-2,6-dimetil-fenoksi)-buterne kiseline (200 mg, 0.63 mmol) i bis(pinakolato)dibor (193 mg, 0.76 mmol) su izreagovani na isti način kao u fazi A primera pripreme 4 da bi se dobilo naslovno jedinjenje (60 mg, 26 %).[0440] 4-(4-Bromo-2,6-dimethyl-phenoxy)-butyric acid ethyl ester (200 mg, 0.63 mmol) and bis(pinacolato)diboron (193 mg, 0.76 mmol) were reacted in the same manner as in Step A of Preparation Example 4 to give the title compound (60 mg, 26%).

[0441] <1>H NMR (CDCl<3>) δ 7.47(2H, s), 4.16(2H, q), 3.80(2H, t), 2.60(2H, t), 2.25(6H, s), 2.14(2H, m), 1.32(12H, s), 1.27(3H, t)[0441] <1>H NMR (CDCl<3>) δ 7.47(2H, s), 4.16(2H, q), 3.80(2H, t), 2.60(2H, t), 2.25(6H, s), 2.14(2H, m), 1.32(12H, s), 1.27(3H, t)

[0443] Primer pripreme 12: etil estar 4-(4-bromo-2,3-difluoro-fenoksi)buterna kiselinaPreparation example 12: 4-(4-bromo-2,3-difluoro-phenoxy)butyric acid ethyl ester

[0444] 4-bromo-2,3-difluorofenol (0.45 g, 2 mmol) je rastvoren u 10 mL DMF-a i rastvor je ohlađen do 0°C. Dodat je NaH (60% u mineralnom ulju, 0.11 g, 2.6 mmol) i mešavina je mešana 30 minuta. Dodat je etil estar 4-bromo-buterne kiseline (0.37 mL, 2.4 mmol), i reakciona mešavina je mešana 16 sati na sobnoj temperaturi. Mešavina je koncentrovana pod smanjenim pritiskom, dodata sa vodenim rastvorom amonijakhlorida i ekstrahovana sa EtOAc. Odvojeni organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.533 g, 76 %).[0444] 4-Bromo-2,3-difluorophenol (0.45 g, 2 mmol) was dissolved in 10 mL of DMF and the solution was cooled to 0°C. NaH (60% in mineral oil, 0.11 g, 2.6 mmol) was added and the mixture was stirred for 30 min. 4-Bromo-butyric acid ethyl ester (0.37 mL, 2.4 mmol) was added, and the reaction mixture was stirred for 16 hours at room temperature. The mixture was concentrated under reduced pressure, added with aqueous ammonia solution and extracted with EtOAc. The separated organic layer was dried with MgSO4 and purified by column chromatography to give the title compound (0.533 g, 76 %).

[0445] <1>H NMR (CDCl<3>) δ 7.19 (1H, m), 6.66 (1H, m), 4.16 (2H, q), 4.09 (2H, t), 2.52 (2H, t), 2.14 (2H, m), 1.26 (3H, t)[0445] <1>H NMR (CDCl<3>) δ 7.19 (1H, m), 6.66 (1H, m), 4.16 (2H, q), 4.09 (2H, t), 2.52 (2H, t), 2.14 (2H, m), 1.26 (3H, t)

[0447] Primer pripreme 13: etil estar 4-[2,3-difluoro-4-(3-hidroksifenil)fenoksi]buterne kiseline[0447] Preparation example 13: 4-[2,3-difluoro-4-(3-hydroxyphenyl)phenoxy]butyric acid ethyl ester

[0448] Etil estar 4-(4-bromo-2,3-difluoro-fenoksi)buterne kiseline dobijen iz primera pripreme 12 (0.108 g, 0.33 mmol) i 3-hidroksifenil borne kiseline (0.059 g, 0.43 mmol) su rastvoreni u 1.7 mL 1,4-dioksana i 2M Na<2>CO<3>vodenog rastvora (0.5 mL, 1 mmol). Mešavini je dodavan 5 minuta N<2>gas. Dodat je Pd(PPh<3>)<4>(0.019 g, 0.016 mmol), i reakciona mešavina je mešana 1 sat pod refluksom. Organski sloj je ekstrahovan saEtOAc i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.089 g, 79 %).[0448] 4-(4-bromo-2,3-difluoro-phenoxy)butyric acid ethyl ester obtained from preparation example 12 (0.108 g, 0.33 mmol) and 3-hydroxyphenyl boric acid (0.059 g, 0.43 mmol) were dissolved in 1.7 mL of 1,4-dioxane and 2M Na<2>CO<3>aqueous solution (0.5 mL, 1 mmol). N<2>gas was added to the mixture for 5 minutes. Pd(PPh<3>)<4> (0.019 g, 0.016 mmol) was added, and the reaction mixture was stirred for 1 hour under reflux. The organic layer was extracted with EtOAc and purified by column chromatography to give the title compound (0.089 g, 79 %).

[0449] <1>H NMR (CDCl<3>) δ 7.29 (1H, t), 7.06 (2H, m), 6.98 (1H, d), 6.84 (1H, dd), 6.78 (1H, m), 5.15 (1H, brs), 4.16 (4H, m), 2.56 (2H, t), 2.17 (2H, m), 1.27 (3H, t)[0449] <1>H NMR (CDCl<3>) δ 7.29 (1H, t), 7.06 (2H, m), 6.98 (1H, d), 6.84 (1H, dd), 6.78 (1H, m), 5.15 (1H, brs), 4.16 (4H, m), 2.56 (2H, t), 2.17 (2H, m), 1.27 (3H, t)

[0451] Primer pripreme 14: 2-hloro-6-(1-piperidil)piridin[0451] Preparation example 14: 2-chloro-6-(1-piperidyl)pyridine

[0452] 2,6-dihloropiridin (2.0 g, 13.5 mmol), piperidin (1.33 mL, 13.5 mmol) i Cs<2>CO<3>(4.4 g, 13.5 mmol) su rastvoreni u 27 mL DMF-a, i mešavina je mešana 16 sati na 80°C. Mešavina je filtrirana kroz Celite, koncentrovana pod smanjenim pritiskom i razblažena vodom. Mešavina je ekstrahovana sa EtOAc i ekstrakt je prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (1.91g, 72 %).[0452] 2,6-Dichloropyridine (2.0 g, 13.5 mmol), piperidine (1.33 mL, 13.5 mmol) and Cs<2>CO<3> (4.4 g, 13.5 mmol) were dissolved in 27 mL of DMF, and the mixture was stirred for 16 hours at 80°C. The mixture was filtered through Celite, concentrated under reduced pressure and diluted with water. The mixture was extracted with EtOAc and the extract was purified by column chromatography to give the title compound (1.91g, 72%).

[0453] <1>H NMR (CDCl<3>) δ 7.34 (1H, t), 6.52 (1H, d), 6.47 (1H, d), 3.52 (4H, m), 1.64 (6H, m)[0453] <1>H NMR (CDCl<3>) δ 7.34 (1H, t), 6.52 (1H, d), 6.47 (1H, d), 3.52 (4H, m), 1.64 (6H, m)

[0455] Primer pripreme 15: 6-hloro-N-fenil-piridin-2-amin[0455] Preparation example 15: 6-chloro-N-phenyl-pyridin-2-amine

[0456] 2,6-dihloropiridin (2.0 g, 13.5 mmol), anilin (1.23 mL, 13.5 mmol), BINAP (0.33 g, 0.53 mmol) i natrijum tert-butoksid (1.82 g, 18.9 mmol) su rastvoreni u 27 mL toluena. Mešavini je dodavan N<2>gas 5 minuta. Dodat je Pd<2>(dba)<3>(0.25 g, 0.27 mmol), i mešavina je mešana 3 sata na 80°C. Mešavina je filtrirana kroz Celite a zatim prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (1.32 g, 48 %).[0456] 2,6-Dichloropyridine (2.0 g, 13.5 mmol), aniline (1.23 mL, 13.5 mmol), BINAP (0.33 g, 0.53 mmol) and sodium tert-butoxide (1.82 g, 18.9 mmol) were dissolved in 27 mL of toluene. N<2>gas was added to the mixture for 5 minutes. Pd<2>(dba)<3> (0.25 g, 0.27 mmol) was added, and the mixture was stirred for 3 hours at 80°C. The mixture was filtered through Celite and then purified by column chromatography to give the title compound (1.32 g, 48 %).

[0457] <1>H NMR (CDCl<3>) δ 7.43 (1H, t), 7.35 (2H, t), 7.27 (2H, m), 7.10 (1H, t), 6.75 (1H, d), 6.73 (1H, d), 6.57 (1H, brs)[0457] <1>H NMR (CDCl<3>) δ 7.43 (1H, t), 7.35 (2H, t), 7.27 (2H, m), 7.10 (1H, t), 6.75 (1H, d), 6.73 (1H, d), 6.57 (1H, brs)

[0459] Primer pripreme 16: 6-hloro-N-ciklopentil-piridin-2-amin[0459] Preparation example 16: 6-chloro-N-cyclopentyl-pyridin-2-amine

[0460] 2,6-dihloropiridin (2 g, 13.5 mmol) je rastvoren u 14 mL piridina, i dodat je ciklopentilamin (4 mL, 40.5 mmol). Reakciona mešavina je mešana 24 sata pod refluksom. Mešavina je koncentrovana pod smanjenim pritiskom a zatim prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (1.2 g, 44 %).[0460] 2,6-Dichloropyridine (2 g, 13.5 mmol) was dissolved in 14 mL of pyridine, and cyclopentylamine (4 mL, 40.5 mmol) was added. The reaction mixture was stirred for 24 hours under reflux. The mixture was concentrated under reduced pressure and then purified by column chromatography to give the title compound (1.2 g, 44 %).

[0461] <1>H NMR (CDCl<3>) δ 7.34 (1H, t), 6.54 (1H, d), 6.25 (1H, d), 4.69 (1H, brs), 3.91 (1H, m), 2.01 (2H, m), 1.72 (2H, m), 1.63 (2H, m), 1.47 (2H, m)[0461] <1>H NMR (CDCl<3>) δ 7.34 (1H, t), 6.54 (1H, d), 6.25 (1H, d), 4.69 (1H, brs), 3.91 (1H, m), 2.01 (2H, m), 1.72 (2H, m), 1.63 (2H, m), 1.47 (2H, m)

[0463] Primer pripreme 17: 2-tert-butilsulfanil-6-hloro-piridin[0463] Preparation example 17: 2-tert-butylsulfanyl-6-chloro-pyridine

[0464] 2,6-dihloropiridin (2.0 g, 13.5 mmol) i Cs<2>CO<3>(8.8 g, 27 mmol) su rastvoreni u 27 mL DMF-a. Dodat je 2-metil-2-propantiol (1.68 mL, 14.8 mmol), i mešavina je mešana 16 sati na 80°C. Čvrste materije su uklonjene i filtrat je koncentrovan pod smanjenim pritiskom da bi se dobilo naslovno jedinjenje (2.4 g, 88 %).[0464] 2,6-Dichloropyridine (2.0 g, 13.5 mmol) and Cs<2>CO<3> (8.8 g, 27 mmol) were dissolved in 27 mL of DMF. 2-Methyl-2-propanethiol (1.68 mL, 14.8 mmol) was added, and the mixture was stirred for 16 hours at 80°C. The solids were removed and the filtrate was concentrated under reduced pressure to give the title compound (2.4 g, 88 %).

[0465] <1>H NMR (CDCl<3>) δ 7.42 (1H, t), 7.15 (1H, d), 7.04 (1H, d), 1.56 (9H, s)[0465] <1>H NMR (CDCl<3>) δ 7.42 (1H, t), 7.15 (1H, d), 7.04 (1H, d), 1.56 (9H, s)

[0466] Primer pripreme 18: 2-hloro-6-(ciklopropilmetilsulfanil)piridinPreparation example 18: 2-chloro-6-(cyclopropylmethylsulfanyl)pyridine

[0467] Faza A: 6-hloropiridin-2-tiol[0467] Phase A: 6-chloropyridin-2-thiol

[0468] 2-tert-butilsulfanil-6-hloro-piridin dobijen iz primera pripreme 17 (1.98 g, 9.8 mmol) je rastvoren u 50 mL acetilhlorida. Polako je dodato 0.05 mL (0.098 mmol) Br2 rastvorenog u odgovarajuća 2.5 ml acetilhlorida i sirćetne kiseline. Mešavina je mešana 4 sata na sobnoj temperaturi, koncentrovana pod smanjenim pritiskom i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.787 g, 55 %).[0468] 2-tert-butylsulfanyl-6-chloro-pyridine obtained from preparation example 17 (1.98 g, 9.8 mmol) was dissolved in 50 mL of acetyl chloride. 0.05 mL (0.098 mmol) of Br2 dissolved in the corresponding 2.5 mL of acetyl chloride and acetic acid was slowly added. The mixture was stirred for 4 hours at room temperature, concentrated under reduced pressure and purified by column chromatography to give the title compound (0.787 g, 55 %).

[0469] <1>H NMR (CDCl<3>) δ 7.57 (2H, m), 7.15 (1H, m)[0469] <1>H NMR (CDCl<3>) δ 7.57 (2H, m), 7.15 (1H, m)

[0471] Faza B: 2-hloro-6-(ciklopropilmetilsulfanil)piridin[0471] Phase B: 2-chloro-6-(cyclopropylmethylsulfanyl)pyridine

[0472] 6-hloropiridin-2-tiol dobijen iz faze A (0.2 g, 1.3 mmol) je rastvoren u 4.6 mL DMF-a. Dodati su Cs<2>CO<3>(0.9 g, 2.6 mmol) i (bromometil)ciklopropan (0.16 mL, 1.6 mmol), i reakciona mešavina je mešana 16 sati na sobnoj temperaturi i dodatnih 30 minuta na 70°C. Mešavina je koncentrovana pod smanjenim pritiskom i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.206 g, 75 %).[0472] The 6-chloropyridin-2-thiol obtained from phase A (0.2 g, 1.3 mmol) was dissolved in 4.6 mL of DMF. Cs<2>CO<3> (0.9 g, 2.6 mmol) and (bromomethyl)cyclopropane (0.16 mL, 1.6 mmol) were added, and the reaction mixture was stirred for 16 hours at room temperature and an additional 30 minutes at 70°C. The mixture was concentrated under reduced pressure and purified by column chromatography to give the title compound (0.206 g, 75 %).

[0473] <1>H NMR (CDCl<3>) δ 7.40 (1H, t), 7.08 (1H, d), 6.98 (1H, d), 3.12 (2H, d), 1.15 (1H, m), 0.59 (2H, m), 0.33 (2H, m)[0473] <1>H NMR (CDCl<3>) δ 7.40 (1H, t), 7.08 (1H, d), 6.98 (1H, d), 3.12 (2H, d), 1.15 (1H, m), 0.59 (2H, m), 0.33 (2H, m)

[0475] Primer pripreme 19: 2-hloro-6-ciklobutilsulfanil-piridin[0475] Preparation example 19: 2-chloro-6-cyclobutylsulfanyl-pyridine

[0476] 6-hloropiridin-2-tiol dobijen iz faze A primera pripreme 18 (0.2 g, 1.3 mmol) je rastvoren u 4.6 mL DMF-a. Dodati su Cs<2>CO<3>(0.9 g, 2.6 mmol) i bromociklobutan (0.16 mL, 1.6 mmol), i reakciona mešavina je mešana 16 sati na sobnoj temperaturi i dodatna 4 sata na 70°C. Mešavina je koncentrovana pod smanjenim pritiskom i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.16 g, 58 %).[0476] 6-Chloropyridine-2-thiol obtained from phase A of Preparation Example 18 (0.2 g, 1.3 mmol) was dissolved in 4.6 mL of DMF. Cs<2>CO<3> (0.9 g, 2.6 mmol) and bromocyclobutane (0.16 mL, 1.6 mmol) were added, and the reaction mixture was stirred for 16 hours at room temperature and an additional 4 hours at 70°C. The mixture was concentrated under reduced pressure and purified by column chromatography to give the title compound (0.16 g, 58 %).

[0477] <1>H NMR (CDCl<3>) δ 7.40 (1H, t), 6.98 (2H, m), 4.30 (1H, m), 2.56 (2H, m), 2.08 (4H, m)[0477] <1>H NMR (CDCl<3>) δ 7.40 (1H, t), 6.98 (2H, m), 4.30 (1H, m), 2.56 (2H, m), 2.08 (4H, m)

[0479] Primer pripreme 20: 2-hloro-6-propilsulfanil-piridin[0479] Preparation example 20: 2-chloro-6-propylsulfanyl-pyridine

[0480] 6-hloropiridin-2-tiol dobijen iz faze A primera pripreme 18 (0.2 g, 1.3 mmol) je rastvoren u 4.6 mL DMF-a. Dodati su Cs<2>CO<3>(0.9 g, 2.6 mmol) i jodopropan (0.16 mL, 1.6 mmol), i reakciona mešavina je mešana 16 sati na sobnoj temperaturi i dodatnih 30 minuta na 70°C. Mešavina je koncentrovana pod smanjenim pritiskom i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.18g, 70 %).[0480] 6-Chloropyridine-2-thiol obtained from phase A of Preparation Example 18 (0.2 g, 1.3 mmol) was dissolved in 4.6 mL of DMF. Cs<2>CO<3> (0.9 g, 2.6 mmol) and iodopropane (0.16 mL, 1.6 mmol) were added, and the reaction mixture was stirred for 16 hours at room temperature and an additional 30 minutes at 70°C. The mixture was concentrated under reduced pressure and purified by column chromatography to give the title compound (0.18g, 70%).

[0481] <1>H NMR (CDCl<3>) δ 7.40 (1H, t), 7.07 (1H, d), 6.97 (1H, d), 3.14 (2H, t), 1.74 (2H, m), 1.04 (3H, t)[0481] <1>H NMR (CDCl<3>) δ 7.40 (1H, t), 7.07 (1H, d), 6.97 (1H, d), 3.14 (2H, t), 1.74 (2H, m), 1.04 (3H, t)

[0483] Primer pripreme 21: 2-hloro-6-izopropoksi-piridin[0483] Preparation example 21: 2-chloro-6-isopropoxy-pyridine

[0484] Izopropanol (0.97 g, 16.1 mmol) je rastvoren u 45 mL THF-a i rastvor je ohlađen do 0°C. Dodat je NaH (55 % u mineralnom ulju, 0.7 g, 16 mmol), i mešavina je mešana 1 sat na sobnoj temperaturi. Dodat je 2,6-dihloropiridin (2.0 g, 13.5 mmol), i reakciona mešavina je mešana 16 sati pod refluksom. Mešavina je ohlađena na sobnoj temperaturi, dodata joj je voda (20 mL) a zatim je ekstrahovana sa EtOAc.[0484] Isopropanol (0.97 g, 16.1 mmol) was dissolved in 45 mL of THF and the solution was cooled to 0°C. NaH (55% in mineral oil, 0.7 g, 16 mmol) was added, and the mixture was stirred for 1 hour at room temperature. 2,6-Dichloropyridine (2.0 g, 13.5 mmol) was added, and the reaction mixture was stirred for 16 h under reflux. The mixture was cooled to room temperature, water (20 mL) was added, and then extracted with EtOAc.

[0485] Odvojeni organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (1.917 g, 82 %).[0485] The separated organic layer was dried with MgSO<4> and purified by column chromatography to give the title compound (1.917 g, 82 %).

[0486] <1>H NMR (CDCl<3>) δ 7.48 (1H, t), 6.83 (1H, d), 6.58 (1H, d), 5.29 (1H, m), 1.34 (6H, d)[0486] <1>H NMR (CDCl<3>) δ 7.48 (1H, t), 6.83 (1H, d), 6.58 (1H, d), 5.29 (1H, m), 1.34 (6H, d)

[0488] Primer pripreme 22: 2-hloro-6-propoksi-piridin[0488] Preparation example 22: 2-chloro-6-propoxy-pyridine

[0489] 30 mL DMF-a je dodato u 6-hloro-2-piridol (2.0 g, 15 mmol), 1-jodopropan (2.75 g, 16 mmol) i K<2>CO<3>(4.27 g, 30 mmol) i reakciona mešavina je mešana 16 sati na 80°C. Mešavina je koncentrovana pod smanjenim pritiskom, dodata joj je voda a zatim je ekstrahovana sa EtOAc. Odvojeni organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (1.146 g, 43 %).[0489] 30 mL of DMF was added to 6-chloro-2-pyridol (2.0 g, 15 mmol), 1-iodopropane (2.75 g, 16 mmol) and K<2>CO<3> (4.27 g, 30 mmol) and the reaction mixture was stirred for 16 hours at 80°C. The mixture was concentrated under reduced pressure, water was added and then extracted with EtOAc. The separated organic layer was dried with MgSO4 and purified by column chromatography to give the title compound (1.146 g, 43 %).

[0490] <1>H NMR (CDCl<3>) δ 7.50 (1H, t), 6.87 (1H, d), 6.63 (1H, d), 4.24 (2H, t), 1.80 (2H, m), 1.02 (3H, t)[0490] <1>H NMR (CDCl<3>) δ 7.50 (1H, t), 6.87 (1H, d), 6.63 (1H, d), 4.24 (2H, t), 1.80 (2H, m), 1.02 (3H, t)

[0492] Primer pripreme 23: 2-hloro-6-(ciklopropilmetoksi)-piridin[0492] Preparation example 23: 2-chloro-6-(cyclopropylmethoxy)-pyridine

[0493] 15 mL DMF-a je dodato u 6-hloro-2-piridol (1.0 g, 7.7 mmol), K<2>CO<3>(2.13 g, 15.4 mmol) i (bromometil)ciklopropan (1.1 g, 8.1 mmol) i reakciona mešavina je mešana 16 sati na 80°C. Mešavina je koncentrovana pod smanjenim pritiskom i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.65 g, 45 %).[0493] 15 mL of DMF was added to 6-chloro-2-pyridol (1.0 g, 7.7 mmol), K<2>CO<3> (2.13 g, 15.4 mmol) and (bromomethyl)cyclopropane (1.1 g, 8.1 mmol) and the reaction mixture was stirred for 16 hours at 80°C. The mixture was concentrated under reduced pressure and purified by column chromatography to give the title compound (0.65 g, 45 %).

[0494] <1>H NMR (CDCl<3>) δ 7.50 (1H, t), 6.87 (1H, d), 6.67 (1H, d), 4.12 (2H, d), 1.26 (1H, m), 0.62 (2H, m), 0.36 (2H, m)[0494] <1>H NMR (CDCl<3>) δ 7.50 (1H, t), 6.87 (1H, d), 6.67 (1H, d), 4.12 (2H, d), 1.26 (1H, m), 0.62 (2H, m), 0.36 (2H, m)

[0496] Primer pripreme 24: 2-hloro-6-(ciklobutoksi)-piridin[0496] Preparation example 24: 2-chloro-6-(cyclobutoxy)-pyridine

[0497] 5 mL DMF-a je dodato u 6-hloro-2-piridol (0.2 g, 1.5 mmol), bromociklobutan (0.26 g, 1.8 mmol) i K<2>CO<3>(0.43 g.3 mmol) i reakciona mešavina je mešana 16 sati na 80°C. Mešavina je koncentrovana pod smanjenim pritiskom i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.28 g, 98 %).[0497] 5 mL of DMF was added to 6-chloro-2-pyridol (0.2 g, 1.5 mmol), bromocyclobutane (0.26 g, 1.8 mmol) and K<2>CO<3> (0.43 g, 3 mmol) and the reaction mixture was stirred for 16 hours at 80°C. The mixture was concentrated under reduced pressure and purified by column chromatography to give the title compound (0.28 g, 98 %).

[0498] <1>H NMR (CDCl<3>) δ 7.49 (1H, t), 6.86 (1H, d), 6.59 (1H, d), 5.16 (1H, m), 2.46 (2H, m), 2.13 (2H, m), 1.83 (1H, m), 1.66 (1H, m)[0498] <1>H NMR (CDCl<3>) δ 7.49 (1H, t), 6.86 (1H, d), 6.59 (1H, d), 5.16 (1H, m), 2.46 (2H, m), 2.13 (2H, m), 1.83 (1H, m), 1.66 (1H, m)

[0500] Primer pripreme 25: etil estar 4-[2-metil-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiselinePreparation example 25: 4-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester

[0501] Faza A: 4-bromo-2-metil-fenol[0501] Phase A: 4-bromo-2-methyl-phenol

[0502] 48% HBr vodeni rastvor (4.8 mL) rastvoren u 4.8 mL DMSO-a je polako dodat o-kresolu (1.04 g, 9.6 mmol) rastvorenom u 9.6 mL sirćetne kiseline. Mešavina je mešana 16 sati na sobnoj temperaturi a zatim je polako dodat vodeni rastvor NaHCO<3>. Mešavina je ekstrahovana sa Et<2>O i ekstrakt je osušen sa MgSO<4>da bi se dobilo naslovno jedinjenje (1.82 g, 99 %).[0502] A 48% aqueous HBr solution (4.8 mL) dissolved in 4.8 mL DMSO was slowly added to o-cresol (1.04 g, 9.6 mmol) dissolved in 9.6 mL acetic acid. The mixture was stirred for 16 hours at room temperature and then an aqueous solution of NaHCO<3> was slowly added. The mixture was extracted with Et<2>O and the extract was dried with MgSO<4> to give the title compound (1.82 g, 99 %).

[0503] <1>H NMR (DMSO-d<6>) δ 9.62 (1H, brs), 7.22 (1H, d), 7.12 (1H, dd), 6.72 (1H, d), 2.09 (3H, s)[0503] <1>H NMR (DMSO-d<6>) δ 9.62 (1H, brs), 7.22 (1H, d), 7.12 (1H, dd), 6.72 (1H, d), 2.09 (3H, s)

[0505] Faza B: 2-metil-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenol[0505] Phase B: 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

[0506] 4.6 mL 1,4-dioksana je dodato u 4-bromo-2-metil-fenol dobijen iz faze A (0.26 g, 1.4 mmol), bis(pinakolato)dibor (0.39 g, 1.5 mmol) i kalijumacetat (0.41 g, 4.1 mmol). Mešavini je dodavan N<2>gas 5 minuta. Dodat je PdCl<2>(dppf)-DCM (0.057 g, 0.07 mmol), i mešavina je mešana 16 sati pod refluksom. Čvrste materije su uklonjene i mešavina je prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.228 g, 70 %).[0506] 4.6 mL of 1,4-dioxane was added to 4-bromo-2-methyl-phenol obtained from phase A (0.26 g, 1.4 mmol), bis(pinacolato)diboron (0.39 g, 1.5 mmol) and potassium acetate (0.41 g, 4.1 mmol). N<2>gas was added to the mixture for 5 minutes. PdCl<2>(dppf)-DCM (0.057 g, 0.07 mmol) was added, and the mixture was stirred for 16 h under reflux. The solids were removed and the mixture was purified by column chromatography to give the title compound (0.228 g, 70 %).

[0507] <1>H NMR (DMSO-d<6>) δ 9.70 (1H, brs), 7.37 (1H, d), 7.32 (1H, dd), 6.75 (1H, d), 2.09 (3H, s), 1.25 (12H, s)[0507] <1>H NMR (DMSO-d<6>) δ 9.70 (1H, brs), 7.37 (1H, d), 7.32 (1H, dd), 6.75 (1H, d), 2.09 (3H, s), 1.25 (12H, s)

[0509] Faza C: etil estar 4-[2-metil-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline [0119] 2-metil-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenol dobijen iz faze B (0.228 g, 0.97 mmol) je rastvoren u 3.2 mL DMF-a. Cs<2>CO<3>(0.8 g, 2.43 mmol) i etil estar 4-bromo-buterne kiseline (0.15 mL, 1.06 mmol) su dodati tome, i mešavina je mešana 16 sati na sobnoj temperaturi. Čvrste materije su uklonjene i mešavina je prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.268 g, 79 %).[0509] Phase C: 4-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester [0119] 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol from phase B (0.228 g, 0.97 mmol) was dissolved in 3.2 mL of DMF. Cs<2>CO<3> (0.8 g, 2.43 mmol) and 4-bromobutyric acid ethyl ester (0.15 mL, 1.06 mmol) were added thereto, and the mixture was stirred for 16 hours at room temperature. The solids were removed and the mixture was purified by column chromatography to give the title compound (0.268 g, 79 %).

[0510] <1>H NMR (CDCl<3>) δ 7.60 (1H, dd), 7.58 (1H, d), 6.79 (1H, d), 4.13 (2H, q), 4.03 (2H, t), 2.53 (2H, t), 2.20 (3H, s), 2.15 (2H, m), 1.33 (12H, s), 1.25 (3H, t)[0510] <1>H NMR (CDCl<3>) δ 7.60 (1H, dd), 7.58 (1H, d), 6.79 (1H, d), 4.13 (2H, q), 4.03 (2H, t), 2.53 (2H, t), 2.20 (3H, s), 2.15 (2H, m), 1.33 (12H, s), 1.25 (3H, t)

[0512] Primer pripreme 26: etil estar 4-[4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)-2-(trifluorometil)fenoksi]buterne kiselinePreparation example 26: 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy]butyric acid ethyl ester

[0513] Faza A: 4-bromo-2-(trifluorometil)fenol[0513] Phase A: 4-bromo-2-(trifluoromethyl)phenol

[0514] 2-hidroksibenzotrifluorid (1.0 g, 6.2 mmol) je rastvoren u 20 mL hloroforma. Br<2>(0.98 g, 6.2 mmol) je polako dodat i mešavina je mešana 16 sati na sobnoj temperaturi. Dodat je vodeni rastvor natrijumtiosulfata i mešavina je ekstrahovana sa DCM-om. Izdvojeni organski sloj je osušen sa MgSO<4>da bi se dobilo naslovno jedinjenje (0.97 g, 65 %).[0514] 2-Hydroxybenzotrifluoride (1.0 g, 6.2 mmol) was dissolved in 20 mL of chloroform. Br<2> (0.98 g, 6.2 mmol) was slowly added and the mixture was stirred for 16 hours at room temperature. Aqueous sodium thiosulfate was added and the mixture was extracted with DCM. The separated organic layer was dried with MgSO<4> to give the title compound (0.97 g, 65 %).

[0515] <1>H NMR (DMSO-d<6>) δ 10.93 (1H, brs), 7.63 (2H, m), 6.99 (1H, dd)[0515] <1>H NMR (DMSO-d<6>) δ 10.93 (1H, brs), 7.63 (2H, m), 6.99 (1H, dd)

[0517] Faza B: 4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)-2-(trifluorometil) fenol[0517] Phase B: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenol

[0518] 13 mL 1,4-dioksana je dodato u 4-bromo-2-(trifluorometil)fenol dobijen iz faze A (0.97 g, 4 mmol), bis(pinakolato)dibor (1.13 g, 4.4 mmol), kalijumacetat (1.18 g, 12 mmol) i DPPF (0.11 g, 0.2 mmol). Mešavini je dodavan N<2>gas 5 minuta. Dodat je PdCl<2>(dppf)-DCM(0.164 g, 0.2 mmol) i mešavina je mešana 1 sat pod refluksom. Mešavina je filtrirana kroz Celite da bi se uklonile čvrste materije, a zatim prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.76 g, 65 %).[0518] 13 mL of 1,4-dioxane was added to 4-bromo-2-(trifluoromethyl)phenol obtained from phase A (0.97 g, 4 mmol), bis(pinacolato)diboron (1.13 g, 4.4 mmol), potassium acetate (1.18 g, 12 mmol) and DPPF (0.11 g, 0.2 mmol). N<2>gas was added to the mixture for 5 minutes. PdCl<2>(dppf)-DCM (0.164 g, 0.2 mmol) was added and the mixture was stirred for 1 hour under reflux. The mixture was filtered through Celite to remove solids and then purified by column chromatography to give the title compound (0.76 g, 65 %).

[0519] <1>H NMR (DMSO-d<6>) δ 11.02 (1H, brs), 7.72 (2H, m), 7.02 (1H, dd), 1.27 (12H, s)[0519] <1>H NMR (DMSO-d<6>) δ 11.02 (1H, brs), 7.72 (2H, m), 7.02 (1H, dd), 1.27 (12H, s)

[0521] Faza C: etil estar 4-[4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)-2-(trifluorometil) fenoksi]buterne kiseline[0521] Phase C: 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy]butyric acid ethyl ester

[0522] 4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)-2-(trifluorometil)fenol dobijen iz faze B (0.36 g, 1.26 mmol) je rastvoren u 4.2 mL DMF-a. Dodati su Cs<2>CO<3>(0.81 g, 2.52 mmol) i etil estar 4-bromobuterne kiseline (0.2 mL, 1.38 mmol) i mešavina je mešana 16 sati na sobnoj temperaturi. Čvrste materije su uklonjene i mešavina je prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.374 g, 74 %).[0522] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenol obtained from phase B (0.36 g, 1.26 mmol) was dissolved in 4.2 mL of DMF. Cs<2>CO<3> (0.81 g, 2.52 mmol) and 4-bromobutyric acid ethyl ester (0.2 mL, 1.38 mmol) were added and the mixture was stirred for 16 hours at room temperature. The solids were removed and the mixture was purified by column chromatography to give the title compound (0.374 g, 74 %).

[0523] <1>H NMR (CDCl<3>) δ 7.99 (1H, d), 7.90 (1H, dd), 6.95 (1H, dd), 4.13 (4H, m), 2.54 (2H, t), 2.14 (2H, m), 1.33 (12H, s), 1.25 (3H, t)[0523] <1>H NMR (CDCl<3>) δ 7.99 (1H, d), 7.90 (1H, dd), 6.95 (1H, dd), 4.13 (4H, m), 2.54 (2H, t), 2.14 (2H, m), 1.33 (12H, s), 1.25 (3H, t)

[0525] Primer pripreme 27: metil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]valerijanske kiseline[0525] Preparation example 27: 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]valeric acid methyl ester

[0526] Faza A: 4-hidroksivalerijanska kiselina[0526] Phase A: 4-hydroxyvaleric acid

[0527] r-valerolakton (0.97 g, 9.68 mmol) je rastvoren u 10 mL 1,4-dioksana. Dodat je IN NaOH vodeni rastvor (10.6 mL, 10.6 mmol) i mešavina je mešana 1 sat. Upotrebom IN HCl vodenog rastvora, pH reakcione mešavine je podešena na 5 i mešavina je ekstrahovana sa EtOAc. Organski sloj je osušen sa MgSO<4>da bi se dobilo naslovno jedinjenje (0.88 g, 74 %).[0527] r-valerolactone (0.97 g, 9.68 mmol) was dissolved in 10 mL of 1,4-dioxane. 1N aqueous NaOH solution (10.6 mL, 10.6 mmol) was added and the mixture was stirred for 1 hour. Using 1N aqueous HCl, the pH of the reaction mixture was adjusted to 5 and the mixture was extracted with EtOAc. The organic layer was dried with MgSO4 to give the title compound (0.88 g, 74 %).

[0528] <1>H NMR (CDCl<3>) δ 3.89 (1H, m), 2.51(2H, t), 1.82 (1H, m), 1.75 (1H, m), 1.24 (3H, d)[0528] <1>H NMR (CDCl<3>) δ 3.89 (1H, m), 2.51 (2H, t), 1.82 (1H, m), 1.75 (1H, m), 1.24 (3H, d)

[0530] Faza B: metil estar 4-hidroksivalerijanske kiseline[0530] Phase B: 4-hydroxyvaleric acid methyl ester

[0531] 4-hidroksivalerijanska kiselina dobijena iz faze A (0.62 g, 5.25 mmol) je rastvorena u 17 mL THF-a, i polako je dodat diazometan (0.25M u Et<2>O, 31 mL, 7.88 mmol). Mešavina je mešana 1 sat na sobnoj temperaturi, a zatim koncentrovana pod smanjenim pritiskom. Koncentrat je prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.42 g, 60 %).[0531] The 4-hydroxyvaleric acid obtained from step A (0.62 g, 5.25 mmol) was dissolved in 17 mL of THF, and diazomethane (0.25 M in Et<2>O, 31 mL, 7.88 mmol) was slowly added. The mixture was stirred for 1 hour at room temperature and then concentrated under reduced pressure. The concentrate was purified by column chromatography to give the title compound (0.42 g, 60 %).

[0532] <1>H NMR (CDCl<3>) δ 3.84 (1H, m), 3.68 (3H, s), 2.46 (2H, t), 1.82 (1H, m), 1.74 (1H, m), 1.21 (3H, d)[0532] <1>H NMR (CDCl<3>) δ 3.84 (1H, m), 3.68 (3H, s), 2.46 (2H, t), 1.82 (1H, m), 1.74 (1H, m), 1.21 (3H, d)

[0534] Faza C: metil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il) fenoksi]valerijanske kiseline[0534] Phase C: 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]valeric acid methyl ester

[0535] Metil estar 4-hidroksivalerijanske kiseline dobijen iz faze B (0.05 g, 0.39 mmol), 2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenol dobijen iz faze B primera pripreme 2 (0.1 g, 0.39 mmol) i trifenilfosfin (0.1 g, 0.39 mmol) su rastvoreni u 4 mL THF-a, i mešavina je polako ohlađena do 0°C. Diizopropil azodikarboksilat (0.077 mL, 0.39 mmol) je polako dodat i reakciona mešavina je mešana 18 sati na sobnoj temperaturi. Mešavina je koncentrovana pod smanjenim pritiskom i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.1 g, 70 %).[0535] 4-hydroxyvaleric acid methyl ester obtained from phase B (0.05 g, 0.39 mmol), 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol obtained from phase B of preparation example 2 (0.1 g, 0.39 mmol) and triphenylphosphine (0.1 g, 0.39 mmol) were dissolved in 4 mL of THF, and the mixture was slowly cooled to 0°C. Diisopropyl azodicarboxylate (0.077 mL, 0.39 mmol) was slowly added and the reaction mixture was stirred for 18 hours at room temperature. The mixture was concentrated under reduced pressure and purified by column chromatography to give the title compound (0.1 g, 70 %).

[0536] <1>H NMR (CDCl<3>) δ 7.31 (2H, m), 4.38 (1H, m), 3.68 (3H, s), 2.59 (2H, t), 2.00 (2H, m), 1.32 (12H, s), 1.25 (3H, d)[0536] <1>H NMR (CDCl<3>) δ 7.31 (2H, m), 4.38 (1H, m), 3.68 (3H, s), 2.59 (2H, t), 2.00 (2H, m), 1.32 (12H, s), 1.25 (3H, d)

[0538] Primer pripreme 28: metil estar 4-[[5-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)-2-piridil]oksi]valerijanske kiseline[0538] Preparation example 28: 4-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]valeric acid methyl ester

[0539] Faza A: metil estar 4-[(5-bromo-2-piridil)oksi]valerijanske kiseline[0539] Phase A: 4-[(5-bromo-2-pyridyl)oxy]valeric acid methyl ester

[0540] 5-bromo-2(1H)-piridon (0.05 g, 0.29 mmol), metil estar 4-hidroksivalerijanske kiseline (0.047 g, 0.29 mmol) i trifenilfosfin (0.075 g, 0.29 mmol) su rastvoreni u 3 mL THF-a. Dodat je diizopropil azodikarboksilat (0.056 mL, 0.29 mmol), i reakciona mešavina je mešana 16 sati na sobnoj temperaturi. Mešavina je koncentrovana pod smanjenim pritiskom i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.051 g, 62 %).[0540] 5-Bromo-2(1H)-pyridone (0.05 g, 0.29 mmol), 4-hydroxyvaleric acid methyl ester (0.047 g, 0.29 mmol) and triphenylphosphine (0.075 g, 0.29 mmol) were dissolved in 3 mL of THF. Diisopropyl azodicarboxylate (0.056 mL, 0.29 mmol) was added, and the reaction mixture was stirred for 16 hours at room temperature. The mixture was concentrated under reduced pressure and purified by column chromatography to give the title compound (0.051 g, 62 %).

[0541] <1>H NMR (CDCl<3>) δ 8.15 (1H, m), 7.60 (1H, m), 6.58 (1H, d), 5.18 (1H, m), 3.65 (3H, s), 2.41 (2H, m), 2.00 (2H, m), 1.31 (3H, d)[0541] <1>H NMR (CDCl<3>) δ 8.15 (1H, m), 7.60 (1H, m), 6.58 (1H, d), 5.18 (1H, m), 3.65 (3H, s), 2.41 (2H, m), 2.00 (2H, m), 1.31 (3H, d)

[0543] Faza B: metil estar metil 4-[[5-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)-2-piridil]oksi]valerijanske kiseline[0543] Phase B: 4-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]valeric acid methyl ester

[0544] Metil estar 4-[(5-bromo-2-piridil)oksi]valerijanske kiseline dobijen iz faze A (0.05 g, 0.17 mmol), bis(pinakolato)dibor (0.048 g, 0.19 mmol) i kalijumacetat (0.067 g, 0.68 mmol) su rastvoreni u 1 mL 1,4-dioksana, i mešavini je dodavan N<2>gas 5 minuta. Dodat je PdCl<2>(dppf)-DCM (0.007 g, 0.009 mmol), i reakciona mešavina je mešana 2 sata na 80°C. Mešavina je filtrirana kroz Celite i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.038 g, 65 %).[0544] 4-[(5-bromo-2-pyridyl)oxy]valeric acid methyl ester obtained from phase A (0.05 g, 0.17 mmol), bis(pinacolato)diboron (0.048 g, 0.19 mmol) and potassium acetate (0.067 g, 0.68 mmol) were dissolved in 1 mL of 1,4-dioxane, and N<2> gas was added to the mixture. 5 minutes. PdCl<2>(dppf)-DCM (0.007 g, 0.009 mmol) was added, and the reaction mixture was stirred for 2 hours at 80°C. The mixture was filtered through Celite and purified by column chromatography to give the title compound (0.038 g, 65 %).

[0545] <1>H NMR (CDCl<3>) δ 8.05 (1H, m), 7.89 (1H, m), 6.64 (1H, d), 5.30 (1H, m), 3.65 (3H, s), 2.44 (2H, m), 2.01 (2H, m), 1.34 (3H, d), 1.26 (12H, s)[0545] <1>H NMR (CDCl<3>) δ 8.05 (1H, m), 7.89 (1H, m), 6.64 (1H, d), 5.30 (1H, m), 3.65 (3H, s), 2.44 (2H, m), 2.01 (2H, m), 1.34 (3H, d), 1.26 (12H, with)

[0547] Primer pripreme 29: metil estar 2-(4-bromo-fenilsulfanil)-propionske kiseline[0547] Preparation example 29: 2-(4-bromo-phenylsulfanyl)-propionic acid methyl ester

[0548] 4-bromo-benzentiol (0.5 g, 2.64 mmol), NaH (60% u mineralnom ulju, 0.11 g, 2.64 mmol) i metil 2-bromopropionat (0.32 mL, 2.91 mmol) su izreagovani na isti način kao u primeru pripreme 12 da bi se dobilo naslovno jedinjenje (0.58 g, 80 %).[0548] 4-Bromo-benzenethiol (0.5 g, 2.64 mmol), NaH (60% in mineral oil, 0.11 g, 2.64 mmol) and methyl 2-bromopropionate (0.32 mL, 2.91 mmol) were reacted in the same manner as in Preparation Example 12 to give the title compound (0.58 g, 80%).

[0549] <1>H-NMR (CDCl<3>) δ 7.43 (2H, d), 7.30 (2H, d), 3.76 (1H, q), 3.66 (3H, s), 1.47 (3H, d).[0549] <1>H-NMR (CDCl<3>) δ 7.43 (2H, d), 7.30 (2H, d), 3.76 (1H, q), 3.66 (3H, s), 1.47 (3H, d).

[0551] Primer pripreme 30: 2-[1-[[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksilmetil ]ciklopropil]acetonitril[0551] Preparation example 30: 2-[1-[[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxylmethyl]cyclopropyl]acetonitrile

[0552] Faza A: [1-(hidroksimetil)ciklopropil]metanol[0552] Phase A: [1-(hydroxymethyl)cyclopropyl]methanol

[0553] LAH (0.28 g, 7.52 mmol) je rastvoren u 10 mL THF-a, i rastvor je ohlađen do -18°C. Dietil 1,1-ciklopropandikarboksilat (1.0 g, 5.37 mmol) u 7 mL THF-a je polako dodat, i reakciona mešavina je mešana 16 sati na sobnoj temperaturi. Dodato je 0.3 mL vode i 0.3 mL 4M NaOH vodenog rastvora. Mešavina je filtrirana Celite-om i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.2 g, 35 %).[0553] LAH (0.28 g, 7.52 mmol) was dissolved in 10 mL of THF, and the solution was cooled to -18°C. Diethyl 1,1-cyclopropanedicarboxylate (1.0 g, 5.37 mmol) in 7 mL of THF was slowly added, and the reaction mixture was stirred for 16 h at room temperature. 0.3 mL of water and 0.3 mL of 4M NaOH aqueous solution were added. The mixture was filtered through Celite and purified by column chromatography to give the title compound (0.2 g, 35 %).

[0554] <1>H NMR (CDCl<3>) δ 3.62 (4H, s), 2.35 (2H, brs), 0.53 (4H, s)[0554] <1>H NMR (CDCl<3>) δ 3.62 (4H, s), 2.35 (2H, brs), 0.53 (4H, s)

[0556] Faza B: [1-[(4-bromo-2.6-difluoro-fenoksi)metil]ciklopropil]metanol[0556] Phase B: [1-[(4-bromo-2.6-difluoro-phenoxy)methyl]cyclopropyl]methanol

[0557] [1-(hidroksimetil)ciklopropil]metanol dobijen iz faze A (0.2 g, 1.96 mmol), 4-bromo-2,6-difluorofenol (0.314 g, 1.5 mmol) i trifenilfosfin (0.393 g, 1.5 mmol) su rastvoreni u 24 mL THF-a. Dodat je diizopropil azokarboksilat (0.3 mL, 1.5 mmol), i reakciona mešavina je mešana 16 sati na sobnoj temperaturi. Mešavina je koncentrovana pod smanjenim pritiskom i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.307 g, 70 %).[0557] [1-(hydroxymethyl)cyclopropyl]methanol obtained from phase A (0.2 g, 1.96 mmol), 4-bromo-2,6-difluorophenol (0.314 g, 1.5 mmol) and triphenylphosphine (0.393 g, 1.5 mmol) were dissolved in 24 mL of THF. Diisopropyl azocarboxylate (0.3 mL, 1.5 mmol) was added, and the reaction mixture was stirred for 16 h at room temperature. The mixture was concentrated under reduced pressure and purified by column chromatography to give the title compound (0.307 g, 70 %).

[0558] <1>H NMR (CDCl<3>) δ 7.08 (2H, m), 4.08 (2H, s), 3.68 (2H, d), 1.84 (1H, t, OH), 0.62 (4H, m)[0558] <1>H NMR (CDCl<3>) δ 7.08 (2H, m), 4.08 (2H, s), 3.68 (2H, d), 1.84 (1H, t, OH), 0.62 (4H, m)

[0560] Faza C: [1-[(4-bromo-2,6-difluoro-fenoksi)metil]ciklopropil]metil metansulfonat[0560] Phase C: [1-[(4-bromo-2,6-difluoro-phenoxy)methyl]cyclopropyl]methyl methanesulfonate

[0561] [1-[(4-bromo-2,6-difluoro-fenoksi)metil]ciklopropil]metanol dobijen iz faze B (0.3 g, 1 mmol) je rastvoren u 5 mL DCM-a, i rastvor je ohlađen do 0 °C. Metansulfonil hlorid (0.09 mL, 1.12 mmol) i TEA (0.21 mL, 1.5 mmol) su sekvencijalno dodati, i mešavina je 40 minuta mešana na 0 °C.5 mL vode je dodato, i mešavina je ekstrahovana sa DCM-om da bi se dobilo naslovno jedinjenje (0.4g, 99 %).[0561] [1-[(4-bromo-2,6-difluoro-phenoxy)methyl]cyclopropyl]methanol obtained from phase B (0.3 g, 1 mmol) was dissolved in 5 mL of DCM, and the solution was cooled to 0 °C. Methanesulfonyl chloride (0.09 mL, 1.12 mmol) and TEA (0.21 mL, 1.5 mmol) were added sequentially, and the mixture was stirred for 40 min at 0 °C. 5 mL of water was added, and the mixture was extracted with DCM to give the title compound (0.4 g, 99 %).

[0562] <1>H NMR (CDCl<3>) δ 7.09 (2H, m), 4.29 (2H, s), 4.01 (2H, s), 3.05 (3H, s), 0.77 (2H, m), 0.73 (2H, m)[0562] <1>H NMR (CDCl<3>) δ 7.09 (2H, m), 4.29 (2H, s), 4.01 (2H, s), 3.05 (3H, s), 0.77 (2H, m), 0.73 (2H, m)

[0564] Faza D: 2-[1-1[(4-bromo-2,6-difluoro-fenoksi)metil]ciklopropil]acetonitril[0564] Phase D: 2-[1-1[(4-bromo-2,6-difluoro-phenoxy)methyl]cyclopropyl]acetonitrile

[0565] [1-[(4-bromo-2,6-difluoro-fenoksi)metil]ciklopropil]metil metan sulfonat dobijen iz faze C (0.4 g, 1 mmol) je rastvoren u 5 mL DMF-a. Dodat je natrijumcijanid (0.054 g, 1.1 mmol), i reakciona mešavina je 16 sati mešana na 60 °C. Mešavina je koncentrovana pod smanjenim pritiskom. Dodata je voda i mešavina je ekstrahovana sa EtOAc. Ekstrakt je prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.205 g, 63 %).[0565] [1-[(4-bromo-2,6-difluoro-phenoxy)methyl]cyclopropyl]methyl methane sulfonate obtained from phase C (0.4 g, 1 mmol) was dissolved in 5 mL of DMF. Sodium cyanide (0.054 g, 1.1 mmol) was added, and the reaction mixture was stirred at 60 °C for 16 h. The mixture is concentrated under reduced pressure. Water was added and the mixture was extracted with EtOAc. The extract was purified by column chromatography to give the title compound (0.205 g, 63 %).

[0566] <1>H NMR (CDCl<3>) δ 7.09 (2H, m), 3.98 (2H, s), 2.72 (2H, s), 0.75 (2H, m), 0.70 (2H, m)[0566] <1>H NMR (CDCl<3>) δ 7.09 (2H, m), 3.98 (2H, s), 2.72 (2H, s), 0.75 (2H, m), 0.70 (2H, m)

[0568] Faza E: 2-[1-[[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]metil]ciklopropil]acetonitril[0568] Phase E: 2-[1-[[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]cyclopropyl]acetonitrile

[0569] 2-[1-[(4-bromo-2,6-difluoro-fenoksi)metil]ciklopropil]acetonitril dobijen iz faze D (0.2 g, 0.67 mmol), bis(pinakolato)dibor (0.172 g, 0.67 mmol), kalijumacetat (0.266 g, 2.71 mmol) i DPPF (0.019 g, 0.033 mmol) su rastvoreni u 4 mL 1,4-dioksana. Mešavini je dodavan 5 minuta N<2>gas. Dodat je PdCl<2>(dppf)-DCM(0.027 g, 0.033 mmol), i mešavina je 2 sata mešana na 80°C. Mešavina je filtrirana kroz Celite i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.185 g, 79 %).[0569] 2-[1-[(4-bromo-2,6-difluoro-phenoxy)methyl]cyclopropyl]acetonitrile obtained from phase D (0.2 g, 0.67 mmol), bis(pinacolato)diboron (0.172 g, 0.67 mmol), potassium acetate (0.266 g, 2.71 mmol) and DPPF (0.019 g, 0.033 mmol) were dissolved in 4 mL of 1,4-dioxane. N<2>gas was added to the mixture for 5 minutes. PdCl<2>(dppf)-DCM (0.027 g, 0.033 mmol) was added, and the mixture was stirred at 80°C for 2 hours. The mixture was filtered through Celite and purified by column chromatography to give the title compound (0.185 g, 79 %).

[0570] <1>H NMR (CDCl<3>) δ 7.32 (2H, m), 4.04 (2H, s), 2.75 (2H, s), 1.33 (12H, s), 0.73 (2H, m), 0.68 (2H, m)[0570] <1>H NMR (CDCl<3>) δ 7.32 (2H, m), 4.04 (2H, s), 2.75 (2H, s), 1.33 (12H, s), 0.73 (2H, m), 0.68 (2H, m)

[0572] Primer pripreme 31: etil estar 4-[[6-(3-hidroksifenil)-3-piridil]oksi]buterne kiselinePreparation example 31: 4-[[6-(3-hydroxyphenyl)-3-pyridyl]oxy]butyric acid ethyl ester

[0573] Faza A: etil estar 4-[(6-bromo-3-piridil)oksilbuterne kiseline[0573] Phase A: 4-[(6-bromo-3-pyridyl)oxybutyric acid ethyl ester

[0574] 2-bromo-5-hidroksipiridin (1.07 g, 6.18 mmol) je rastvoren u 20 mL DMF-a. Dodati su K<2>CO<3>(1.7 g, 12.4 mmol) i etil estar 4-bromo-buterne kiseline (1.2 g, 6.18 mmol), i reakciona mešavina je mešana 16 sati na sobnoj temperaturi. Mešavina je koncentrovana pod smanjenim pritiskom. Dodata je voda i mešavina je ekstrahovana sa EtOAc da bi se dobilo naslovno jedinjenje (1.67 g, 94 %).[0574] 2-Bromo-5-hydroxypyridine (1.07 g, 6.18 mmol) was dissolved in 20 mL of DMF. K<2>CO<3> (1.7 g, 12.4 mmol) and 4-bromobutyric acid ethyl ester (1.2 g, 6.18 mmol) were added, and the reaction mixture was stirred for 16 h at room temperature. The mixture is concentrated under reduced pressure. Water was added and the mixture was extracted with EtOAc to give the title compound (1.67 g, 94 %).

[0575] <1>H NMR (CDCl<3>) δ 8.04 (1H, m), 7.36 (1H, d), 7.09 (1H, m), 4.15 (2H, q), 4.04 (2H, t), 2.51 (2H, t), 2.13 (2H, m), 1.26 (3H, t)[0575] <1>H NMR (CDCl<3>) δ 8.04 (1H, m), 7.36 (1H, d), 7.09 (1H, m), 4.15 (2H, q), 4.04 (2H, t), 2.51 (2H, t), 2.13 (2H, m), 1.26 (3H, t)

[0577] Faza B: etil estar 4-[[6-(3-hidroksifenil)-3-piridil]oksi]buterne kiseline[0577] Phase B: 4-[[6-(3-hydroxyphenyl)-3-pyridyl]oxy]butyric acid ethyl ester

[0578] Etil estar 4-[(6-bromo-3-piridil)oksi]buterne kiseline dobijen iz faze A (0.3 g, 1 mmol) i 3-hidroksifenilborna kiselina (0.172 g, 1.25 mmol) su rastvoreni u 3 mL 1,2-dimetoksietana i Na<2>CO<3>(2M vodeni rastvor, 1.6 mL, 3.2 mmol). Mešavini je dodavan N<2>gas 5minuta. Dodat je PdCl<2>(PPh<3>)<2>(0.036 g, 0.052 mmol), i reakciona mešavina je 3 sata mešana na 80°C. Dodata je voda i mešavina je ekstrahovana sa EtOAc. Organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.129 g, 41 %).[0578] 4-[(6-bromo-3-pyridyl)oxy]butyric acid ethyl ester obtained from phase A (0.3 g, 1 mmol) and 3-hydroxyphenylboronic acid (0.172 g, 1.25 mmol) were dissolved in 3 mL of 1,2-dimethoxyethane and Na<2>CO<3> (2M aqueous solution, 1.6 mL, 3.2 mmol). N gas was added to the mixture for 5 minutes. PdCl<2>(PPh<3>)<2> (0.036 g, 0.052 mmol) was added, and the reaction mixture was stirred at 80°C for 3 hours. Water was added and the mixture was extracted with EtOAc. The organic layer was dried with MgSO4 and purified by column chromatography to give the title compound (0.129 g, 41 %).

[0579] <1>H NMR (CDCl<3>) δ 8.34 (1H, m), 7.62 (1H, d), 7.48 (1H, m), 7.41 (1H, m), 7.29 (1H, t), 7.25 (1H, m), 6.85 (1H, m), 5.75 (1H, brs), 4.16 (2H, q), 4.10 (2H, t), 2.54 (2H, t), 2.16 (2H, m), 1.26 (3H, t)[0579] <1>H NMR (CDCl<3>) δ 8.34 (1H, m), 7.62 (1H, d), 7.48 (1H, m), 7.41 (1H, m), 7.29 (1H, t), 7.25 (1H, m), 6.85 (1H, m), 5.75 (1H, brs), 4.16 (2H, q), 4.10 (2H, t), 2.54 (2H, t), 2.16 (2H, m), 1.26 (3H, t)

[0581] Primer pripreme 32: 2'-fenoksi-bifenil-4-ol[0581] Preparation example 32: 2'-phenoxy-biphenyl-4-ol

[0582] 2-fenoksifenilborna kiselina (0.033 g, 0.15 mmol) i 4-jodofenol (0.034 g, 0.15 mmol) su rastvoreni u 3 mL H<2>O, i mešavini je dodavan N<2>gas 5 minuta. Dodati su Pd/C (katalitička količina) i K<2>CO<3>(0.064 g, 0.46 mmol), i reakciona mešavina je mešana 16 sati na sobnoj temperaturi. Dodat je 1N HCl i mešavina je ekstrahovana sa EtOAc. Odvojeni organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni koloni (eluent, EtOAc/Hex = 1/4) da bi se dobilo naslovno jedinjenje (0.022 g, 55 %).[0582] 2-phenoxyphenylboronic acid (0.033 g, 0.15 mmol) and 4-iodophenol (0.034 g, 0.15 mmol) were dissolved in 3 mL of H<2>O, and N<2>gas was added to the mixture for 5 minutes. Pd/C (catalytic amount) and K<2>CO<3> (0.064 g, 0.46 mmol) were added, and the reaction mixture was stirred for 16 hours at room temperature. 1N HCl was added and the mixture was extracted with EtOAc. The separated organic layer was dried with MgSO4 and purified by column chromatography (eluent, EtOAc/Hex = 1/4) to give the title compound (0.022 g, 55 %).

[0584] <1>H-NMR (CDCl<3>) δ 7.46(3H, m), 7.25(3H, m), 7.20(1H, m), 7.00(2H, 6.90(2H, m), 6.89(2H, m), 4.65(1H, s)[0584] <1>H-NMR (CDCl<3>) δ 7.46(3H, m), 7.25(3H, m), 7.20(1H, m), 7.00(2H, 6.90(2H, m), 6.89(2H, m), 4.65(1H, s)

[0586] Primer pripreme 33: 4-(2-izopropilsulfanil-piridin-3-il)-fenol[0586] Preparation example 33: 4-(2-isopropylsulfanyl-pyridin-3-yl)-phenol

[0587] Faza A: 3-hloro-2-izopropilsulfanil-piridin[0587] Phase A: 3-chloro-2-isopropylsulfanyl-pyridine

[0588] NaH (60 %) (0.07 g, 1.75 mmol) je na 0°C polako u kapima dodavan izopropiltiolu (0.102 g, 1.351 mmol) rastvorenom u suvom DMF(2 ml). Mešavina je mešana 30 minuta, dodata sudu napunjenom sa 2,3-dihloropiridinom (0.53 g, 3.58 mmol), i mešana na sobnoj temperaturi 1 sat. Nakon dodavanja NH<4>Cl vodenog rastvora, organski sloj je izdvojen ekstrahovanjem sa EtOAc. Organski sloj je osušen bezvodnim MgSO<4>i prečišćen hromatografijom na koloni (eluent, EtOAc/ Hex = 1/4) da bi se dobilo naslovno jedinjenje (0.062 g, 24 %).[0588] NaH (60%) (0.07 g, 1.75 mmol) was slowly added dropwise at 0°C to isopropylthiol (0.102 g, 1.351 mmol) dissolved in dry DMF (2 ml). The mixture was stirred for 30 minutes, added to a vessel charged with 2,3-dichloropyridine (0.53 g, 3.58 mmol), and stirred at room temperature for 1 hour. After addition of NH<4>Cl aqueous solution, the organic layer was separated by extraction with EtOAc. The organic layer was dried over anhydrous MgSO4 and purified by column chromatography (eluent, EtOAc/Hex = 1/4) to give the title compound (0.062 g, 24 %).

[0589] <1>H-NMR (CDCl<3>) δ 8.35(1H, m), 7.52(1H, m), 6.94(1H, m), 4.05(1H, m), 1.43(6H, d)[0589] <1>H-NMR (CDCl<3>) δ 8.35(1H, m), 7.52(1H, m), 6.94(1H, m), 4.05(1H, m), 1.43(6H, d)

[0591] Faza B: 2-izopropilsulfanil-3-(4-metoksi-fenil)-piridin[0591] Phase B: 2-isopropylsulfanyl-3-(4-methoxy-phenyl)-pyridine

[0592] 3-hloro-2-izopropilsulfanil-piridin dobijen iz faze A (0.02 g, 0.10 mmol) i (4-metoksi-fenil)-borna kiselina (0.024 g, 0.15 mmol) su rastvoreni u DMF-u-u. Mešavini je dodavan 5 minuta N<2>gas. Dodati su Pd<2>(dba)<3>(katalitička količina) i Sphos (katalitička količina), i reakciona mešavina je 16 sati mešana na 80°C. Nakon dodavanja NaCl vodenog rastvora, mešavina je ekstrahovana sa EtOAc. Odvojeni organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni (eluent, EtOAc/Hex = 1/4) da bi se dobilo naslovno jedinjenje (0.01 g, 37 %).[0592] 3-chloro-2-isopropylsulfanyl-pyridine obtained from phase A (0.02 g, 0.10 mmol) and (4-methoxy-phenyl)-boronic acid (0.024 g, 0.15 mmol) were dissolved in DMF. N<2>gas was added to the mixture for 5 minutes. Pd<2>(dba)<3>(catalytic amount) and Sphos (catalytic amount) were added, and the reaction mixture was stirred at 80°C for 16 hours. After addition of NaCl aqueous solution, the mixture was extracted with EtOAc. The separated organic layer was dried with MgSO4 and purified by column chromatography (eluent, EtOAc/Hex = 1/4) to give the title compound (0.01 g, 37 %).

[0593] <1>H-NMR (CDCl<3>) δ 8.41(1H, m), 7.35(3H, m), 7.02(1H, m), 6.95(2H, m), 4.06(1H, m), 3.84(3H, s), 1.35(6H, d)[0593] <1>H-NMR (CDCl<3>) δ 8.41(1H, m), 7.35(3H, m), 7.02(1H, m), 6.95(2H, m), 4.06(1H, m), 3.84(3H, s), 1.35(6H, d)

[0595] Faza C: 4-(2-izopropilsulfanil-piridin-3-il)-fenol[0595] Phase C: 4-(2-isopropylsulfanyl-pyridin-3-yl)-phenol

[0596] 2-izopropilsulfanil-3-(4-metoksi-fenil)-piridin dobijen iz faze B (0.02 g, 0.07 mmol) je rastvoren u DCM-u-u(3 mL), i rastvor je ohlađen do -78°C. BBr<3>(1.0 M u DCM-u, 0.116 mL, 0.11 mmol) je polako dodat, i mešavina je mešana 3 sata na sobnoj temperaturi. Nakon završetka reakcije, mešavina je ohlađena do -20°C. Metanol je dodat ostatku radi razblaženja. Mešavina je ekstrahovana sa DCM-om. Organski sloj je osušen sa MgSO<4>i koncentrovan pod smanjenim pritiskom. Dobijen ostatak je prečišćen hromatografijom na koloni (eluent, EtOAc/Hex = 1/3) da bi se dobilo naslovno jedinjenje (15 mg, 75 %).[0596] 2-Isopropylsulfanyl-3-(4-methoxy-phenyl)-pyridine obtained from phase B (0.02 g, 0.07 mmol) was dissolved in DCM (3 mL), and the solution was cooled to -78°C. BBr<3> (1.0 M in DCM, 0.116 mL, 0.11 mmol) was added slowly, and the mixture was stirred for 3 hours at room temperature. After completion of the reaction, the mixture was cooled to -20°C. Methanol was added to the residue for dilution. The mixture was extracted with DCM. The organic layer was dried with MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluent, EtOAc/Hex = 1/3) to give the title compound (15 mg, 75 %).

[0597] <1>H-NMR (CDCl<3>) δ 8.41(1H, m), 7.34(1H, m), 7.26(2H, m), 7.02(1H, m), 6.89(2H, m), 4.79(1H, s), 4.05(1H, m), 1.35(6H, d)[0597] <1>H-NMR (CDCl<3>) δ 8.41(1H, m), 7.34(1H, m), 7.26(2H, m), 7.02(1H, m), 6.89(2H, m), 4.79(1H, s), 4.05(1H, m), 1.35(6H, d)

[0599] Primer pripreme 34: 3,5-difluoro-2'-fenoksi-bifenil-4-ol[0599] Preparation example 34: 3,5-difluoro-2'-phenoxy-biphenyl-4-ol

[0600] Faza A: 3,5-difluoro-4-metoksi-2'-fenoksi-bifenil[0600] Phase A: 3,5-difluoro-4-methoxy-2'-phenoxy-biphenyl

[0601] 2-fenoksifenilborna kiselina (0.045 g, 0.21 mmol)i 5-bromo-1,3-difluoro-2-metoksi-benzen (0.031 g, 0.14 mmol) su rastvoreni u izopropil alkoholu/vodi (1/1). Dodati su Pd/C(katalitička količina) i Na<3>PO<4>12H<2>O(0.186 g, 0.49 mmol), i mešavina je mešana 1 sat na 80 °. Mešavina je filtrirana kroz Celite, i ekstrahovana sa EtOAc da bi se izdvojio organski sloj. Organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni (eluent, EtOAc/Hex = 1/20) da bi se dobilo naslovno jedinjenje (0.026 g, 40 %).[0601] 2-phenoxyphenylboronic acid (0.045 g, 0.21 mmol) and 5-bromo-1,3-difluoro-2-methoxy-benzene (0.031 g, 0.14 mmol) were dissolved in isopropyl alcohol/water (1/1). Pd/C (catalytic amount) and Na<3>PO<4>12H<2>O (0.186 g, 0.49 mmol) were added, and the mixture was stirred for 1 hour at 80 °. The mixture was filtered through Celite, and extracted with EtOAc to separate the organic layer. The organic layer was dried with MgSO4 and purified by column chromatography (eluent, EtOAc/Hex = 1/20) to give the title compound (0.026 g, 40 %).

[0602] <1>H-NMR (CDCl<3>) δ 7.40(1H, m), 7.30(3H, m), 7.20(1H, m), 7.11(2H, m), 7.05(1H, m), 6.97(1H, m), 6.91(2H, m), 4.00(3H, s)[0602] <1>H-NMR (CDCl<3>) δ 7.40(1H, m), 7.30(3H, m), 7.20(1H, m), 7.11(2H, m), 7.05(1H, m), 6.97(1H, m), 6.91(2H, m), 4.00(3H, s)

[0604] Faza B: 3.5-difluoro-2'-fenoksi-bifenil-4-ol[0604] Phase B: 3,5-difluoro-2'-phenoxy-biphenyl-4-ol

[0605] 3,5-difluoro-4-metoksi-2'-fenoksi-bifenil dobijen iz faze A (0.026 g, 0.083 mmol) je izreagovan na isti način kao u fazi C primera pripreme 33 da bi se dobilo naslovno jedinjenje (0.018 g, 72 %).[0605] The 3,5-difluoro-4-methoxy-2'-phenoxy-biphenyl obtained from phase A (0.026 g, 0.083 mmol) was reacted in the same manner as in phase C of Preparation Example 33 to give the title compound (0.018 g, 72 %).

[0606] <1>H-NMR (CDCl<3>) δ 7.40(1H, m), 7.30(3H, m), 7.20(1H, m), 7.11(2H, m), 7.05(1H, m), 6.96(1H, m), 6.91(2H, m), 5.08(1H, s)[0606] <1>H-NMR (CDCl<3>) δ 7.40(1H, m), 7.30(3H, m), 7.20(1H, m), 7.11(2H, m), 7.05(1H, m), 6.96(1H, m), 6.91(2H, m), 5.08(1H, s)

[0608] Primer pripreme 35: 4-(2-ciklopentilsulfanil-piridin-3-il)-fenol[0608] Preparation example 35: 4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenol

[0609] Faza A: 3-hloro-2-ciklopentilsulfanil-piridin[0609] Phase A: 3-chloro-2-cyclopentylsulfanyl-pyridine

[0610] Ciklopentil tiol (0.477 g 4.67 mmol) je rastvoren u suvom DMF-u(2 ml) i rastvor je ohlađen do 0°C. NaH(60 %)(0.24 g, 6.03 mmol) je polako dodavan u kapima i mešavina je mešana 30 minuta. Mešavina je dodata u sud napunjen 2,3-dihloropiridinom (0.69 g, 4.67 mmol) i mešana 1 sat na sobnoj temperaturi. NH<4>Cl vodeni rastvor je dodat reakcionoj mešavini i mešavina je ekstrahovana sa EtOAc da bi se izdvojio organski sloj. Organski sloj je osušen bezvodnim MgSO<4>i prečišćen hromatografijom na koloni (eluent, EtOAc/ Hex = 1/4) da bi se dobilo naslovno jedinjenje (0.61 g, 61 %).[0610] Cyclopentyl thiol (0.477 g 4.67 mmol) was dissolved in dry DMF (2 ml) and the solution was cooled to 0°C. NaH(60 %) (0.24 g, 6.03 mmol) was slowly added dropwise and the mixture was stirred for 30 min. The mixture was added to a vessel filled with 2,3-dichloropyridine (0.69 g, 4.67 mmol) and stirred for 1 hour at room temperature. NH<4>Cl aqueous solution was added to the reaction mixture and the mixture was extracted with EtOAc to separate the organic layer. The organic layer was dried over anhydrous MgSO4 and purified by column chromatography (eluent, EtOAc/Hex = 1/4) to give the title compound (0.61 g, 61 %).

[0611] <1>H-NMR (CDCl<3>) δ 8.33(1H, m), 7.51(1H, m), 6.92(1H, m), 4.09(1H, m), 2.23(2H, m), 1.79(2H, m), 1.66(4H, m)[0611] <1>H-NMR (CDCl<3>) δ 8.33(1H, m), 7.51(1H, m), 6.92(1H, m), 4.09(1H, m), 2.23(2H, m), 1.79(2H, m), 1.66(4H, m)

[0613] Faza B: 2-ciklopentilsulfanil-3-(4-metoksi-fenil)-piridin[0613] Phase B: 2-cyclopentylsulfanyl-3-(4-methoxy-phenyl)-pyridine

[0614] 3-hloro-2-ciklopentilsulfanil-piridin dobijen iz faze A (0.057 g, 0.266 mmol) je izreagovan na isti način kao u fazi B primera pripreme 33 da bi se dobilo naslovno jedinjenje (0.046 g, 61 %).[0614] The 3-chloro-2-cyclopentylsulfanyl-pyridine obtained from phase A (0.057 g, 0.266 mmol) was reacted in the same manner as in phase B of Preparation Example 33 to give the title compound (0.046 g, 61 %).

[0615] <1>H-NMR (CDCl<3>) δ 8.41(1H, m), 7.36(3H, m), 7.01(1H, m), 6.96(2H, m), 4.08(1H, m), 3.85(3H, s), 2.19(2H, m), 1.70(2H, m), 1.66(4H, m)[0615] <1>H-NMR (CDCl<3>) δ 8.41(1H, m), 7.36(3H, m), 7.01(1H, m), 6.96(2H, m), 4.08(1H, m), 3.85(3H, s), 2.19(2H, m), 1.70(2H, m), 1.66(4H, m)

[0617] Faza C: 4-(2-ciklopentilsulfanil-piridin-3-il)-fenol[0617] Phase C: 4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenol

[0618] 2-ciklopentilsulfanil-3-(4-metoksi-fenil)-piridin dobijen iz faze B (0.046 g, 0.161 mmol) je izreagovan na isti način kao u fazi C primera pripreme 33 da bi se dobilo naslovno jedinjenje (0.024 g, 55 %).[0618] 2-Cyclopentylsulfanyl-3-(4-methoxy-phenyl)-pyridine obtained from step B (0.046 g, 0.161 mmol) was reacted in the same manner as step C of Preparation Example 33 to give the title compound (0.024 g, 55%).

[0619] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.33(3H, m), 7.01(1H, m), 6.98(2H, m), 4.87(1H, s), 4.09(1H, m), 2.18(2H, m), 1.70(2H, m), 1.66(4H, m)[0619] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.33(3H, m), 7.01(1H, m), 6.98(2H, m), 4.87(1H, s), 4.09(1H, m), 2.18(2H, m), 1.70(2H, m), 1.66(4H, m)

[0621] Primer pripreme 36: 3-jodo-2-fenoksi-piridin[0621] Preparation example 36: 3-iodo-2-phenoxy-pyridine

[0622] 2-fluoro-3-jodo-piridin (0.054 g, 0.24 mmol) i Cs<2>CO<3>(0.158 g, 0.266 mmol) ifenol (0.025 g, 0.266 mmol) su rastvoreni u 2 mL DMF-a. Reakciona mešavina je mešana na 80°C 16 sati. Dodat je vodeni rastvor NaCl i mešavina je ekstrahovana sa EtOAc da bi se izdvojio organski sloj. Organski sloj je osušen bezvodnim MgSO<4>i prečišćen hromatografijom na koloni (eluent, EtOAc/ Hex = 1/7) da bi se dobilo naslovno jedinjenje (0.058 g, 71 %).[0622] 2-fluoro-3-iodo-pyridine (0.054 g, 0.24 mmol) and Cs<2>CO<3> (0.158 g, 0.266 mmol) and phenol (0.025 g, 0.266 mmol) were dissolved in 2 mL of DMF. The reaction mixture was stirred at 80°C for 16 hours. Aqueous NaCl was added and the mixture was extracted with EtOAc to separate the organic layer. The organic layer was dried over anhydrous MgSO4 and purified by column chromatography (eluent, EtOAc/Hex = 1/7) to give the title compound (0.058 g, 71 %).

[0623] <1>H-NMR (CDCl<3>) δ 8.15(1H, m), 8.08(1H, m), 7.40(2H, m), 7.26(1H, m), 7.15(2H, m), 6.75(1H, m)[0623] <1>H-NMR (CDCl<3>) δ 8.15(1H, m), 8.08(1H, m), 7.40(2H, m), 7.26(1H, m), 7.15(2H, m), 6.75(1H, m)

[0625] Primer pripreme 37: 3-jodo-2-izopropoksi-piridin[0625] Preparation example 37: 3-iodo-2-isopropoxy-pyridine

[0626] Izopropil alkohol (0.043 g, 717 mmol) je rastvoren u suvom DMF-u(3 ml), i na 0 °C NaH(60 %)(0.03 g, 0.71 mmol) je polako dodavan u kapima. Mešavina je mešana 30 minuta. Reakciona mešavina je dodata u sud napunjen 2-fluoro-3-jodo-piridinom(0.10 g, 0.44 mmol), i mešana je 1 sat na sobnoj temperaturi. Dodat je NH<4>Cl vodeni rastvor, i mešavina je ekstrahovana sa EtOAc da bi se izdvojio organski sloj. Organski sloj je osušen bezvodnim MgSO<4>i prečišćen hromatografijom na koloni (eluent, EtOAc/Hex = 1/4) da bi se dobilo naslovno jedinjenje (0.029 g, 24 %).[0626] Isopropyl alcohol (0.043 g, 717 mmol) was dissolved in dry DMF (3 ml), and at 0 °C NaH(60 %) (0.03 g, 0.71 mmol) was slowly added dropwise. The mixture was stirred for 30 minutes. The reaction mixture was added to a vessel filled with 2-fluoro-3-iodo-pyridine (0.10 g, 0.44 mmol), and stirred for 1 hour at room temperature. Aqueous NH<4>Cl was added, and the mixture was extracted with EtOAc to separate the organic layer. The organic layer was dried over anhydrous MgSO4 and purified by column chromatography (eluent, EtOAc/Hex = 1/4) to give the title compound (0.029 g, 24 %).

[0627] <1>H-NMR (CDCl<3>) δ 8.08(1H, m), 8.00(1H, m), 6.59(1H, m), 5.27(1H, m), 1.38(6H, d)[0627] <1>H-NMR (CDCl<3>) δ 8.08(1H, m), 8.00(1H, m), 6.59(1H, m), 5.27(1H, m), 1.38(6H, d)

[0629] Primer pripreme 38: 2-ciklopentoksi-3-jodo-piridin[0629] Preparation example 38: 2-cyclopentoxy-3-iodo-pyridine

[0630] Ciklopentanol i 2-fluoro-3-jodo-piridin (0.10 g, 0.44 mmol) su izreagovani na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (0.091 g, 70 %).[0630] Cyclopentanol and 2-fluoro-3-iodo-pyridine (0.10 g, 0.44 mmol) were reacted in the same manner as in Preparation Example 37 to give the title compound (0.091 g, 70 %).

[0631] <1>H-NMR (CDCl<3>) δ 8.09(1H, m), 7.99(1H, m), 6.59(1H, m), 5.43(1H, m), 2.00(2H, m), 1.94(4H, m), 1.66(2H, m)[0631] <1>H-NMR (CDCl<3>) δ 8.09(1H, m), 7.99(1H, m), 6.59(1H, m), 5.43(1H, m), 2.00(2H, m), 1.94(4H, m), 1.66(2H, m)

[0633] Primer pripreme 39: 2-ciklopentilsulfanil-3-jodo-piridin[0633] Preparation example 39: 2-cyclopentylsulfanyl-3-iodo-pyridine

[0634] 2-fluoro-3-jodo-piridin (0.065 g, 0.29 mmol), Cs<2>CO<3>(0.19 g, 0.58 mmol) i ciklopentiltiol (0.03 g, 0.291 mmol) su rastvoreni u 2 mL DMF-a. Reakciona mešavina je mešana na 80°C 2 sata. Dodat je vodeni rastvor NaCl i mešavina je ekstrahovana sa EtOAc da bi se izdvojio organski sloj. Organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni (eluent, EtOAc/Hex = 1/4) da bi se dobilo naslovno jedinjenje (0.053 g, 65 %).[0634] 2-Fluoro-3-iodo-pyridine (0.065 g, 0.29 mmol), Cs<2>CO<3> (0.19 g, 0.58 mmol) and cyclopentylthiol (0.03 g, 0.291 mmol) were dissolved in 2 mL of DMF. The reaction mixture was stirred at 80°C for 2 hours. Aqueous NaCl was added and the mixture was extracted with EtOAc to separate the organic layer. The organic layer was dried with MgSO4 and purified by column chromatography (eluent, EtOAc/Hex = 1/4) to give the title compound (0.053 g, 65 %).

[0635] <1>H-NMR (CDCl<3>) δ 8.38(1H, m), 7.89(1H, m), 6.68(1H, m), 4.00(1H, m), 2.22(2H, m), 1.80(2H, m), 1.66(4H, m)[0635] <1>H-NMR (CDCl<3>) δ 8.38(1H, m), 7.89(1H, m), 6.68(1H, m), 4.00(1H, m), 2.22(2H, m), 1.80(2H, m), 1.66(4H, m)

[0637] Primer pripreme 40: 2-ciklopropilmetoksi-3-jodo-piridin[0637] Preparation example 40: 2-cyclopropylmethoxy-3-iodo-pyridine

[0638] Ciklopropil-metanol (0.089 g, 1.23 mmol) je rastvoren u suvom DMF-u(2 ml), i na 0°C NaH(60 %)(0.054g, 1.35 mmol) je polako dodavan u kapima. Mešavina je mešana 30 minuta,polako je dodata sudu napunjenom sa 2-fluoro-3-jodo-piridinom (0.137 g, 0.617 mmol) i zatim je mešana 1 sat na sobnoj temperaturi. Dodat je NH<4>Cl vodeni rastvor i mešavina je ekstrahovana sa EtOAc da bi se izdvojio organski sloj. Organski sloj je osušen bezvodnim MgSO<4>i prečišćen hromatografijom na koloni (eluent, EtOAc/Hex = 1/5) da bi se dobilo naslovno jedinjenje (0.141 g, 83 %).[0638] Cyclopropyl methanol (0.089 g, 1.23 mmol) was dissolved in dry DMF (2 ml), and at 0 °C NaH(60 %) (0.054 g, 1.35 mmol) was slowly added dropwise. The mixture was stirred for 30 minutes, slowly added to a vessel filled with 2-fluoro-3-iodo-pyridine (0.137 g, 0.617 mmol) and then stirred for 1 hour at room temperature. Aqueous NH<4>Cl was added and the mixture was extracted with EtOAc to separate the organic layer. The organic layer was dried over anhydrous MgSO4 and purified by column chromatography (eluent, EtOAc/Hex = 1/5) to give the title compound (0.141 g, 83 %).

[0639] <1>H-NMR (CDCl<3>) δ 8.07(1H, m), 8.00(1H, m), 6.61(1H, m), 4.20(2H, d), 1.32(1H, m), 0.60(2H, m), 0.39(2H, m)[0639] <1>H-NMR (CDCl<3>) δ 8.07(1H, m), 8.00(1H, m), 6.61(1H, m), 4.20(2H, d), 1.32(1H, m), 0.60(2H, m), 0.39(2H, m)

[0641] Primer pripreme 41: 2-ciklopropilmetilsulfanil-3-(3,5-difluoro-4-metoksi-fenil)-piridinPreparation example 41: 2-cyclopropylmethylsulfanyl-3-(3,5-difluoro-4-methoxy-phenyl)-pyridine

[0642] Faza A: 3-jodo-2-(4-metoksi-benzilsulfanil)-piridin[0642] Phase A: 3-iodo-2-(4-methoxy-benzylsulfanyl)-pyridine

[0643] 2-fluoro-3-jodo-piridin (0.42 g, 1.8 mmol) i (4-metoksifenil)metantiol (0.43 g, 2.8 mmol) su izreagovani na isti način kao u primeru pripreme 12 da bi se dobilo naslovno jedinjenje (0.56 g, 84%).[0643] 2-Fluoro-3-iodo-pyridine (0.42 g, 1.8 mmol) and (4-methoxyphenyl)methanethiol (0.43 g, 2.8 mmol) were reacted in the same manner as in Preparation Example 12 to give the title compound (0.56 g, 84%).

[0644] <1>H-NMR (CDCl<3>) δ 8.43 (1H, m), 7.93 (1H, m), 7.32 (2H, d), 6.85 (2H, d), 6.74 (1H, m), 4.35 (2H, s), 3.79 (3H, s)[0644] <1>H-NMR (CDCl<3>) δ 8.43 (1H, m), 7.93 (1H, m), 7.32 (2H, d), 6.85 (2H, d), 6.74 (1H, m), 4.35 (2H, s), 3.79 (3H, s)

[0646] Faza B: 3-(3.5-difluoro-4-metoksi-fenil)-2-(4-metoksi-benzilsulfanil)-piridin[0646] Phase B: 3-(3,5-difluoro-4-methoxy-phenyl)-2-(4-methoxy-benzylsulfanyl)-pyridine

[0647] 3-jodo-2-(4-metoksi-benzilsulfanil)-piridin dobijen iz faze A (0.1 g, 0.28 mmol) i 2-(3,5-difluoro-4-metoksi-fenil)-4,4,5,5-tetrametil-[1,3,2]dioksaborolan dobijen iz primera pripreme 238 (0.11 g, 0.42 mmol) su izreagovani na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.08 g, 77%).[0647] 3-iodo-2-(4-methoxy-benzylsulfanyl)-pyridine obtained from phase A (0.1 g, 0.28 mmol) and 2-(3,5-difluoro-4-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane obtained from preparation example 238 (0.11 g, 0.42 mmol) were reacted in the same way as in phase A of Example 28 to give the title compound (0.08 g, 77%).

[0648] <1>H-NMR (CDCl<3>) δ 8.47 (1H, m), 7.36 (1H, m), 7.30 (2H, d), 7.07 (1H, m), 6.96 (2H, m), 6.81 (2H, d), 4.38 (2H, s), 4.03 (3H, s), 3.78 (3H, s)[0648] <1>H-NMR (CDCl<3>) δ 8.47 (1H, m), 7.36 (1H, m), 7.30 (2H, d), 7.07 (1H, m), 6.96 (2H, m), 6.81 (2H, d), 4.38 (2H, s), 4.03 (3H, s), 3.78 (3H, s)

[0650] Faza C: 3-(3.5-difluoro-4-metoksi-fenil)-piridin-2-tiol[0650] Phase C: 3-(3,5-difluoro-4-methoxy-phenyl)-pyridine-2-thiol

[0651] 3-(3,5-difluoro-4-metoksi-fenil)-2-(4-metoksi-benzilsulfanil)-piridin dobijen iz faze B (0.033 g, 0.097 mmol) je rastvoren u TFA-u (2 ml). Anizol (0.5 ml) i triflična kiselina (0.2 mL) su polako dodati, i mešavina je 1 sat mešana na 70°C. Na 0 °C, vodeni rastvor natrijumbikarbonata je polako dodat i mešavina je ekstrahovana sa EtOAc. Organski sloj je osušen sa MgSO<4>, uparen pod smanjenim pritiskom i rekristalizovan sa Et<2>O da bi se dobilo naslovno jedinjenje (0.033 g, 61 %).[0651] 3-(3,5-difluoro-4-methoxy-phenyl)-2-(4-methoxy-benzylsulfanyl)-pyridine obtained from step B (0.033 g, 0.097 mmol) was dissolved in TFA (2 ml). Anisole (0.5 mL) and triflic acid (0.2 mL) were added slowly, and the mixture was stirred at 70°C for 1 hour. At 0 °C, aqueous sodium bicarbonate was added slowly and the mixture was extracted with EtOAc. The organic layer was dried with MgSO<4> , evaporated under reduced pressure and recrystallized from Et<2>O to give the title compound (0.033 g, 61 %).

[0652] <1>H-NMR (DMSO-d<6>) δ 7.72(1H, m), 7.57(1H, m), 7.42(2H, m), 6.84(1H, m), 3.96 (3H, s)[0652] <1>H-NMR (DMSO-d<6>) δ 7.72(1H, m), 7.57(1H, m), 7.42(2H, m), 6.84(1H, m), 3.96 (3H, s)

[0654] Faza D: 2-ciklopropilmetilsulfanil-3-(3.5-difluoro-4-metoksi-fenil)-piridin[0654] Phase D: 2-cyclopropylmethylsulfanyl-3-(3,5-difluoro-4-methoxy-phenyl)-pyridine

[0655] 3-(3,5-difluoro-4-metoksi-fenil)-piridin-2-tiol dobijen iz faze C (0.033 g, 0.13 mmol) je rastvoren u suvom DMF-u(1.5 ml), i na 0°C NaH(60 %)(0.01 g, 0.195 mmol) je polako dodavan u kapima. Mešavina je mešana 30 minuta. Bromometilciklopropan (0.021 g, 0.156 mmol) je polako dodat na 0 °C, i reakciona mešavina je mešana 2 sata na sobnoj temperaturi. NH<4>Cl vodeni rastvor je dodat, i mešavina je ekstrahovana sa EtOAc da bi se izdvojio organski sloj. Organski sloj je osušen sa MgSO<4>, prečišćen hromatografijom na koloni (eluent, EtOAc/Hex=1/5) da bi se dobilo naslovno jedinjenje (0.032 g, 82 %).[0655] The 3-(3,5-difluoro-4-methoxy-phenyl)-pyridin-2-thiol obtained from step C (0.033 g, 0.13 mmol) was dissolved in dry DMF (1.5 ml), and at 0°C NaH(60%) (0.01 g, 0.195 mmol) was slowly added dropwise. The mixture was stirred for 30 minutes. Bromomethylcyclopropane (0.021 g, 0.156 mmol) was added slowly at 0 °C, and the reaction mixture was stirred for 2 h at room temperature. NH<4>Cl aqueous solution was added, and the mixture was extracted with EtOAc to separate the organic layer. The organic layer was dried with MgSO<4> , purified by column chromatography (eluent, EtOAc/Hex=1/5) to give the title compound (0.032 g, 82 %).

[0656] <1>H-NMR (CDCl<3>) δ 8.42(1H, m), 7.33(1H, m), 7.00(3H, m), 4.06(3H, s), 3.12(2H, d), 1.12(1H, m), 0.57(2H, m), 0.29(2H, m)[0656] <1>H-NMR (CDCl<3>) δ 8.42(1H, m), 7.33(1H, m), 7.00(3H, m), 4.06(3H, s), 3.12(2H, d), 1.12(1H, m), 0.57(2H, m), 0.29(2H, m)

[0657] Primer pripreme 42: 2-ciklobutilsulfanil-3-(4-metoksi-fenil)-piridin[0657] Preparation example 42: 2-cyclobutylsulfanyl-3-(4-methoxy-phenyl)-pyridine

[0658] Faza A: 2-(4-metoksi-benzilsulfanil)-3-(4-metoksi-fenil)-piridin[0658] Phase A: 2-(4-methoxy-benzylsulfanyl)-3-(4-methoxy-phenyl)-pyridine

[0659] 3-jodo-2-(4-metoksi-benzilsulfanil)-piridin dobijen iz faze A primera pripreme 41 (0.1 g, 0.28 mmol) i (4-metoksifenil)borna kiselina (0.085 g, 0.56 mmol) su izreagovani na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.075 g, 79%).[0659] 3-Iodo-2-(4-methoxy-benzylsulfanyl)-pyridine obtained from Phase A of Preparation Example 41 (0.1 g, 0.28 mmol) and (4-methoxyphenyl)boronic acid (0.085 g, 0.56 mmol) were reacted in the same manner as in Phase A of Example 28 to give the title compound (0.075 g, 79%).

[0660] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.36 (1H, m), 7.33 (4H, m), 7.05 (1H, m), 6.93 (2H, d), 6.80 (2H, d), 4.36 (2H, s), 3.83 (3H, s), 3.76 (3H, s)[0660] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.36 (1H, m), 7.33 (4H, m), 7.05 (1H, m), 6.93 (2H, d), 6.80 (2H, d), 4.36 (2H, s), 3.83 (3H, s), 3.76 (3H, s)

[0662] Faza B: 3-(4-metoksi-fenil)-piridin-2-tiol[0662] Phase B: 3-(4-methoxy-phenyl)-pyridine-2-thiol

[0663] 2-(4-metoksi-benzilsulfanil)-3-(4-metoksi-fenil)-piridin dobijen iz faze A (0.212 g, 0.628 mmol) je izreagovan na isti način kao u fazi C primera pripreme 41 da bi se dobilo naslovno jedinjenje (0.109 g, 80 %).[0663] 2-(4-Methoxy-benzylsulfanyl)-3-(4-methoxy-phenyl)-pyridine obtained from Phase A (0.212 g, 0.628 mmol) was reacted in the same manner as in Phase C of Preparation Example 41 to give the title compound (0.109 g, 80 %).

[0664] <1>H-NMR (DMSO-d<6>) δ 7.65(1H, m), 7.55(2H, d), 7.48(1H, m), 6.93(2H, d), 6.82(1H, m), 3.78 (3H, s)[0664] <1>H-NMR (DMSO-d<6>) δ 7.65(1H, m), 7.55(2H, d), 7.48(1H, m), 6.93(2H, d), 6.82(1H, m), 3.78 (3H, s)

[0666] Faza C: 2-ciklobutilsulfanil-3-(4-metoksi-fenil)-piridin[0666] Phase C: 2-cyclobutylsulfanyl-3-(4-methoxy-phenyl)-pyridine

[0667] 3-(4-metoksi-fenil)-piridin-2-tiol dobijen iz faze B (0.212 g, 0.628 mmol), NaH (0.012 g, 0.294 mmol) i bromo-ciklobutan (0.024 g, 0.176 mmol) su izreagovani na isti način kao u fazi D primera pripreme 41 da bi se dobilo naslovno jedinjenje (0.0094 g, 24 %).[0667] 3-(4-Methoxy-phenyl)-pyridine-2-thiol obtained from Step B (0.212 g, 0.628 mmol), NaH (0.012 g, 0.294 mmol) and bromo-cyclobutane (0.024 g, 0.176 mmol) were reacted in the same manner as in Step D of Preparation Example 41 to give the title compound (0.0094 g, 24 %).

[0668] <1>H-NMR (CDCl<3>) δ 8.37(1H, m), 7.34(3H, m), 7.02(3H, m), 4.42(1H, m), 3.86(3H, s), 2.49(2H, m), 2.03(4H, m)[0668] <1>H-NMR (CDCl<3>) δ 8.37(1H, m), 7.34(3H, m), 7.02(3H, m), 4.42(1H, m), 3.86(3H, s), 2.49(2H, m), 2.03(4H, m)

[0670] Primer pripreme 43: 2-ciklopropilmetilsulfanil-3-(4-metoksi-fenil)-piridin[0670] Preparation example 43: 2-cyclopropylmethylsulfanyl-3-(4-methoxy-phenyl)-pyridine

[0671] 2-(4-metoksi-benzilsulfanil)-3-(4-metoksi-fenil)-piridin dobijen iz faze A primera pripreme 42 (0.04 g, 0.184 mmol) je izreagovan na isti način kao u fazama C i D primera pripreme 41 da bi se dobilo naslovno jedinjenje (0.02 g, 44 %).[0671] 2-(4-Methoxy-benzylsulfanyl)-3-(4-methoxy-phenyl)-pyridine obtained from Step A of Preparative Example 42 (0.04 g, 0.184 mmol) was reacted in the same manner as in Steps C and D of Preparative Example 41 to give the title compound (0.02 g, 44%).

[0672] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.37(3H, m), 7.02(3H, m), 4.09(2H, m), 3.86(3H, s), 1.09(1H, m), 0.54(2H, m), 0.27(2H, m)[0672] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.37(3H, m), 7.02(3H, m), 4.09(2H, m), 3.86(3H, s), 1.09(1H, m), 0.54(2H, m), 0.27(2H, m)

[0674] Primer pripreme 44: 2-ciklobutilsulfanil-3-jodo-piridin[0674] Preparation example 44: 2-cyclobutylsulfanyl-3-iodo-pyridine

[0675] Faza A: ciklobutantiol[0675] Phase A: cyclobutanethiol

[0676] Magnezijum (0.99 g, 40.74 mmol) je rastvoren u THF-u (20 mL). Na 50°C, ciklobutilbromid (5.0 g, 37.03 mmol) u THF-u(5 mL) je polako dodat i mešavina je mešana 2 sata pod refluksom. Na 0°C, sumpor (1.06 g, 33.33 mmol) je polako dodat i mešavina je mešana 2 sata na 50°C. Na 0°C, LAH (0.843 g, 22.22 mmol) je polako dodat i mešavina je mešana 30 minuta pod refluksom. Na 0°C, vodeni rastvor amonijakhlorida (20 mL) i IN HCl (20 mL) je korišćen za završetak reakcije. Mešavina je ekstrahovana sa Et<2>O (30 ml*3) da bi se izdvojili organski slojevi. Organski slojevi su osušeni sa MgSO<4>i korišćeni za sledeću reakciju.[0676] Magnesium (0.99 g, 40.74 mmol) was dissolved in THF (20 mL). At 50 °C, cyclobutyl bromide (5.0 g, 37.03 mmol) in THF (5 mL) was added slowly and the mixture was stirred for 2 h under reflux. At 0 °C, sulfur (1.06 g, 33.33 mmol) was added slowly and the mixture was stirred for 2 hours at 50 °C. At 0°C, LAH (0.843 g, 22.22 mmol) was added slowly and the mixture was stirred for 30 min under reflux. At 0°C, an aqueous solution of ammonia chloride (20 mL) and IN HCl (20 mL) was used to complete the reaction. The mixture was extracted with Et<2>O (30 ml*3) to separate the organic layers. The organic layers were dried with MgSO<4> and used for the next reaction.

[0678] Faza B: 2-ciklobutilsulfanil-3-jodo-piridin[0678] Phase B: 2-cyclobutylsulfanyl-3-iodo-pyridine

[0679] Ciklobutantiol dobijen iz faze A (0.069 g, 0.782 mmol) i 2-fluoro-3-jodo-piridin (0.1 g, 0.43 mmol) su rastvoreni u DMF-u (3 mL). Dodat je Cs<2>CO<3>(0.26 g, 0.86 mmol), i reakciona mešavina je mešana uz zagrevanje na 80°C. Dodat je NaCl vodeni rastvor i mešavina je ekstrahovana sa EtOAc. Organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni (eluent, EtOAc/Hex = 1/4) da bi se dobilo naslovno jedinjenje (0.115 g, 91 %).[0679] Cyclobutanethiol obtained from phase A (0.069 g, 0.782 mmol) and 2-fluoro-3-iodo-pyridine (0.1 g, 0.43 mmol) were dissolved in DMF (3 mL). Cs<2>CO<3> (0.26 g, 0.86 mmol) was added, and the reaction mixture was stirred while heating to 80°C. Aqueous NaCl was added and the mixture was extracted with EtOAc. The organic layer was dried with MgSO4 and purified by column chromatography (eluent, EtOAc/Hex = 1/4) to give the title compound (0.115 g, 91 %).

[0680] <1>H-NMR (CDCl<3>) δ 8.36(1H, m), 7.90(1H, m), 6.69(1H, m), 4.33(1H, m), 2.54(2H, m), 2.14(2H, m), 2.05(2H, m)[0680] <1>H-NMR (CDCl<3>) δ 8.36(1H, m), 7.90(1H, m), 6.69(1H, m), 4.33(1H, m), 2.54(2H, m), 2.14(2H, m), 2.05(2H, m)

[0682] Primer pripreme 45: 3-(4-metoksi-fenil)-2-propilsulfanil-piridin[0682] Preparation example 45: 3-(4-methoxy-phenyl)-2-propylsulfanyl-pyridine

[0683] 3-(4-metoksi-fenil)-piridin-2-tiol dobijen iz faze B primera pripreme 42 (0.053 g, 0.243 mmol), NaH (0.02 g, 0.487 mmol) i 1-jodo-propan (0.049 g, 0.292 mmol) su izreagovani na isti način kao u fazi D primera pripreme 41 da bi se dobilo naslovno jedinjenje (0.023 g, 36 %).[0683] 3-(4-Methoxy-phenyl)-pyridine-2-thiol obtained from Step B of Preparative Example 42 (0.053 g, 0.243 mmol), NaH (0.02 g, 0.487 mmol) and 1-iodo-propane (0.049 g, 0.292 mmol) were reacted in the same manner as in Step D of Preparative Example 41 to give the title compound. (0.023 g, 36 %).

[0684] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.36(3H, m), 7.03(1H, m), 6.98(2H, m), 3.86(3H, s), 3.13 (2H, m), 1.68(2H, m), 1.01(3H, m)[0684] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.36(3H, m), 7.03(1H, m), 6.98(2H, m), 3.86(3H, s), 3.13 (2H, m), 1.68(2H, m), 1.01(3H, m)

[0686] Primer pripreme 46: 1-bromo-2-izopropoksi-benzen[0686] Preparation example 46: 1-bromo-2-isopropoxy-benzene

[0687] 2-bromo-fenol (0.373 g, 2.15 mmol) i 2-bromo-propan (0.291 g, 2.371 mmol) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.257 g, 55 %).[0687] 2-Bromo-phenol (0.373 g, 2.15 mmol) and 2-bromo-propane (0.291 g, 2.371 mmol) were reacted in the same manner as in Step B of Preparation Example 44 to give the title compound (0.257 g, 55%).

[0688] <1>H-NMR (CDCl<3>) δ 7.52(1H, m), 7.25(1H, m), 6.91(1H, m), 6.80(1H, m), 4.54(1H, m), 1.38(6H, d)[0688] <1>H-NMR (CDCl<3>) δ 7.52(1H, m), 7.25(1H, m), 6.91(1H, m), 6.80(1H, m), 4.54(1H, m), 1.38(6H, d)

[0690] Primer pripreme 47: 1-bromo-2-ciklobutoksi-benzen[0690] Preparation example 47: 1-bromo-2-cyclobutoxy-benzene

[0691] 2-bromo-fenol (0.235 g, 1.35 mmol) i bromo-ciklobutan (0.201 g, 1.49 mmol) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.061 g, 19 %).[0691] 2-Bromo-phenol (0.235 g, 1.35 mmol) and bromo-cyclobutane (0.201 g, 1.49 mmol) were reacted in the same manner as in Step B of Preparation Example 44 to give the title compound (0.061 g, 19 %).

[0692] <1>H-NMR (CDCl<3>) δ 7.53(1H, m), 7.19(1H, m), 6.76(1H, m), 6.80(1H, m), 4.68(1H, m), 2.46 (2H, m), 2.27(2H, m), 1.88(1H, m), 1.68(1H, m)[0692] <1>H-NMR (CDCl<3>) δ 7.53(1H, m), 7.19(1H, m), 6.76(1H, m), 6.80(1H, m), 4.68(1H, m), 2.46 (2H, m), 2.27(2H, m), 1.88(1H, m), 1.68(1H, m)

[0694] Primer pripreme 48: 1-bromo-2-ciklopropilmetoksi-benzen[0694] Preparation example 48: 1-bromo-2-cyclopropylmethoxy-benzene

[0695] 2-bromo-fenol (0.235 g, 1.35 mmol) i bromometil-ciklopropan (0.201 g, 1.49 mmol) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.267 g, 86 %).[0695] 2-Bromo-phenol (0.235 g, 1.35 mmol) and bromomethyl-cyclopropane (0.201 g, 1.49 mmol) were reacted in the same manner as in Step B of Preparation Example 44 to give the title compound (0.267 g, 86 %).

[0696] <1>H-NMR (CDCl<3>) δ 7.54(1H, m), 7.22(1H, m), 6.90(1H, m), 6.83(1H, m), 3.89 (2H, d), 1.31(1H, m), 0.63(2H, m), 0.40(2H, m)[0696] <1>H-NMR (CDCl<3>) δ 7.54(1H, m), 7.22(1H, m), 6.90(1H, m), 6.83(1H, m), 3.89 (2H, d), 1.31(1H, m), 0.63(2H, m), 0.40(2H, m)

[0697] Primer pripreme 49: 1-bromo-2-ciklopentoksi-benzen[0697] Preparation example 49: 1-bromo-2-cyclopentoxy-benzene

[0698] 2-bromo-fenol (0.366 g, 2.11 mmol) i bromo-ciklopentan (0.341 g, 2.32 mmol) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.369 g, 72 %).[0698] 2-Bromo-phenol (0.366 g, 2.11 mmol) and bromo-cyclopentane (0.341 g, 2.32 mmol) were reacted in the same manner as in Step B of Preparation Example 44 to give the title compound (0.369 g, 72 %).

[0699] <1>H-NMR (CDCl<3>) δ 7.51(1H, m), 7.25(1H, m), 6.88(1H, m), 6.78(1H, m), 4.80(1H, m), 1.88(6H, m), 1.65(2H, m)[0699] <1>H-NMR (CDCl<3>) δ 7.51(1H, m), 7.25(1H, m), 6.88(1H, m), 6.78(1H, m), 4.80(1H, m), 1.88(6H, m), 1.65(2H, m)

[0701] Primer pripreme 50: etil estar 4-bromo-2-metil-buterne kiseline[0701] Preparation example 50: 4-bromo-2-methyl-butyric acid ethyl ester

[0702] Faza A: etil estar (E)-4-benziloksi-2-metil-2-butenoične kiseline[0702] Phase A: (E)-4-benzyloxy-2-methyl-2-butenoic acid ethyl ester

[0703] Benziloksi-acetaldehid (0.95 g, 6.35 mmol) je rastvoren u benzenu (21 mL), na sobnoj temperaturi, dodat je (1-etoksikarboniletiliden)trifenilfosporan (2.76 g, 7.63 mmol). Mešavina je 16 sati mešana na 70°C. Nakon završetka reakcije, mešavina je koncentrovana pod smanjenim pritiskom i prečišćena hromatografijom na koloni (eluent, EtOAc/Hex = 1/4) da bi se dobilo naslovno jedinjenje (1.31 g, 94 %).[0703] Benzyloxy-acetaldehyde (0.95 g, 6.35 mmol) was dissolved in benzene (21 mL), at room temperature, (1-ethoxycarbonylethylidene)triphenylphosphorane (2.76 g, 7.63 mmol) was added. The mixture was stirred for 16 hours at 70°C. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by column chromatography (eluent, EtOAc/Hex = 1/4) to give the title compound (1.31 g, 94 %).

[0704] <1>H-NMR (CDCl<3>) δ 7.35(5H, m), 6.86(1H, m), 4.54(2H, s), 4.19(4H, m), 1.81(3H, m), 1.28(3H, m)[0704] <1>H-NMR (CDCl<3>) δ 7.35(5H, m), 6.86(1H, m), 4.54(2H, s), 4.19(4H, m), 1.81(3H, m), 1.28(3H, m)

[0706] Faza B: etil estar 4-hidroksi-2-metil-buterne kiseline[0706] Phase B: 4-hydroxy-2-methyl-butyric acid ethyl ester

[0707] Etil estar (E)-4-benziloksi-2-metil-2-butenoične kiseline dobijen iz faze A (1.31 g, 5.97 mmol) je rastvoren u EtOAc/MeOH(8/2)(20 mL), i dodat je 10% Pd/C(0.13 g). Mešavina je mešana 12 sati pod H<2>atmosferom na sobnoj temperaturi. Nakon završetka reakcije, mešavina je filtrirana Celite-om, koncentrovana pod smanjenim pritiskom i prečišćena hromatografijom na koloni (eluent, EtOAc/Hex = 1/2) da bi se dobilo naslovno jedinjenje (0.726 g, 98 %).[0707] (E)-4-benzyloxy-2-methyl-2-butenoic acid ethyl ester obtained from phase A (1.31 g, 5.97 mmol) was dissolved in EtOAc/MeOH(8/2)(20 mL), and 10% Pd/C (0.13 g) was added. The mixture was stirred for 12 hours under H<2>atmosphere at room temperature. After completion of the reaction, the mixture was filtered through Celite, concentrated under reduced pressure and purified by column chromatography (eluent, EtOAc/Hex = 1/2) to give the title compound (0.726 g, 98 %).

[0708] <1>H-NMR (CDCl<3>) δ 4.13(2H, m), 3.68(2H, m), 2.62(1H, m), 1.19(1H, m), 1.70(1H, m), 1.56(1H, m), 1.24(3H, m), 1.18(3H, d)[0708] <1>H-NMR (CDCl<3>) δ 4.13(2H, m), 3.68(2H, m), 2.62(1H, m), 1.19(1H, m), 1.70(1H, m), 1.56(1H, m), 1.24(3H, m), 1.18(3H, d)

[0710] Faza C: etil estar 4-bromo-2-metil-buterne kiseline[0710] Phase C: 4-bromo-2-methyl-butyric acid ethyl ester

[0711] NBS (2.14 g, 12.05 mmol) je rastvoren u DCM-u (10 ml), i dodat je trifenilfosfin (2.94 g, 11.22 mmol). Mešavina je mešana 10 minuta. A zatim su dodati piridin (0.38 g, 4.80 mmol) i etil estar 4-hidroksi-2-metil-buterne kiseline (0.586 g, 4.00 mmol) dobijen iz faze B. Mešavina je mešana 16 sati. Nakon završetka reakcije, mešavina je koncentrovana pod smanjenim pritiskom i prečišćena hromatografijom na koloni (eluent, EtOAc/Hex = 1/4) da bi se dobila smanjena količina naslovnog jedinjenja (0.061 g, 7.3%).[0711] NBS (2.14 g, 12.05 mmol) was dissolved in DCM (10 ml), and triphenylphosphine (2.94 g, 11.22 mmol) was added. The mixture was stirred for 10 minutes. And then pyridine (0.38 g, 4.80 mmol) and 4-hydroxy-2-methyl-butyric acid ethyl ester (0.586 g, 4.00 mmol) obtained from phase B were added. The mixture was stirred for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by column chromatography (eluent, EtOAc/Hex = 1/4) to give a reduced amount of the title compound (0.061 g, 7.3%).

[0712] <1>H-NMR (CDCl<3>) δ 4.13(2H, m), 3.41(2H, m), 2.67(1H, m), 2.27(1H, m), 1.91(1H, m), 1.26(3H, m), 1.19(3H, d)[0712] <1>H-NMR (CDCl<3>) δ 4.13(2H, m), 3.41(2H, m), 2.67(1H, m), 2.27(1H, m), 1.91(1H, m), 1.26(3H, m), 1.19(3H, d)

[0714] Primer pripreme 51: 4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-difluoro-fenol[0714] Preparation example 51: 4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenol

[0715] 2-ciklobutilsulfanil-3-jodo-piridin (0.193 g, 0.66 mmol) dobijen u primeru pripreme 44 i 2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenol (0.254 g, 0.992 mmol) dobijen u fazi B primera pripreme 2 su izreagovani na isti način kao u fazi A primera 50 da bi se dobilo naslovno jedinjenje (0.078 g, 40 %).[0715] 2-cyclobutylsulfanyl-3-iodo-pyridine (0.193 g, 0.66 mmol) obtained in preparation example 44 and 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.254 g, 0.992 mmol) obtained in phase B of preparation example 2 were reacted in the same way as in phase A of Example 50 to give the title compound (0.078 g, 40 %).

[0716] <1>H-NMR (CDCl<3>) δ 8.39(1H, m), 7.30(1H, m), 6.98(3H, m), 5.15(1H, s), 4.40(1H, m), 2.49(2H, m), 2.02(4H, m)[0716] <1>H-NMR (CDCl<3>) δ 8.39(1H, m), 7.30(1H, m), 6.98(3H, m), 5.15(1H, s), 4.40(1H, m), 2.49(2H, m), 2.02(4H, m)

[0718] Primer pripreme 52: etil estar 2-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenoksimetil]-ciklopropankarboksilne kiseline[0718] Preparation example 52: 2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-cyclopropanecarboxylic acid ethyl ester

[0719] Faza A: etil estar (E/Z)-4-benziloksi-but-2-pelargonska kiselina[0719] Phase A: (E/Z)-4-benzyloxy-but-2-pelargonic acid ethyl ester

[0720] Benziloksi-acetaldehid (0.95 g, 6.35 mmol) i etil 2-(trifenilfosforaniliden)acetat (1.36 g, 3.92 mmol) su izreagovani na isti način kao u fazi A primera pripreme 50 da bi se dobilo naslovno jedinjenje (E/Z mešavina) (0.043 g, 40 %).[0720] Benzyloxy-acetaldehyde (0.95 g, 6.35 mmol) and ethyl 2-(triphenylphosphoranylidene)acetate (1.36 g, 3.92 mmol) were reacted in the same manner as in Step A of Preparation Example 50 to give the title compound (E/Z mixture) (0.043 g, 40%).

[0721] <1>H-NMR (CDCl<3>) δ 7.34(5H, m), 6.96(0.62H, m), 6.42(0.38H, m), 6.13(0.62H, m), 5.82(0.38H, m), 4.56(2H, s), 4.19(4H, m), 1.27(3H, m)[0721] <1>H-NMR (CDCl<3>) δ 7.34(5H, m), 6.96(0.62H, m), 6.42(0.38H, m), 6.13(0.62H, m), 5.82(0.38H, m), 4.56(2H, s), 4.19(4H, m), 1.27(3H, m)

[0723] Faza B: etil estar 2-benziloksimetil-ciklopropankarboksilne kiseline[0723] Phase B: 2-benzyloxymethyl-cyclopropanecarboxylic acid ethyl ester

[0724] Nakon što je etil estar (E/Z)-4-benziloksi-but-2-pelargonske kiseline (0.36 g, 1.63 mmol) dobijen u fazi A rastvoren u THF-u (5 mL), dodat je diazometan (30 mL, 8.23 mmol, 0.25M Et<2>O). Nakon što je reaktant ohlađen do 0-5°C, polako je dodat paladijum(II) acetat (0.022 g, 0.098 mmol), i mešavina je mešana 1 sat na sobnoj temperaturi. Nakon završetka reakcije, reaktantu je dodata voda a zatim je ekstrahovan. Organski sloj je koncentrovan pod smanjenim pritiskom i ostatak je prečišćen hromatografijom na koloni (eluent: EtOAc/Hex = 1/4) da bi se dobilo naslovno jedinjenje (0.119 g, 31 %).[0724] After (E/Z)-4-benzyloxy-but-2-pelargonic acid ethyl ester (0.36 g, 1.63 mmol) obtained in phase A was dissolved in THF (5 mL), diazomethane (30 mL, 8.23 mmol, 0.25M Et<2>O) was added. After the reactant was cooled to 0-5°C, palladium(II) acetate (0.022 g, 0.098 mmol) was added slowly, and the mixture was stirred for 1 hour at room temperature. After the completion of the reaction, water was added to the reactant and then it was extracted. The organic layer was concentrated under reduced pressure and the residue was purified by column chromatography (eluent: EtOAc/Hex = 1/4) to give the title compound (0.119 g, 31 %).

[0725] <1>H-NMR (CDCl<3>) δ 7.32(5H, m), 4.51(2H, s), 4.10(2H, m), 3.41(2H, m), 1.70(1H, m), 1.55(1H, m), 1.24(4H, m), 0.85(1H, m)[0725] <1>H-NMR (CDCl<3>) δ 7.32(5H, m), 4.51(2H, s), 4.10(2H, m), 3.41(2H, m), 1.70(1H, m), 1.55(1H, m), 1.24(4H, m), 0.85(1H, m)

[0727] Faza C: etil estar 2-hidroksimetil- ciklopropankarboksilne kiseline[0727] Phase C: 2-hydroxymethyl-cyclopropanecarboxylic acid ethyl ester

[0728] Etil estar 2-benziloksimetil-ciklopropankarboksilne kiseline (0.119 g, 0.50 mmol) dobijen u fazi B je izreagovan na isti način kao u fazi B primera pripreme 50 da bi se dobilo naslovno jedinjenje (0.067 g, 91 %).[0728] 2-Benzyloxymethyl-cyclopropanecarboxylic acid ethyl ester (0.119 g, 0.50 mmol) obtained in phase B was reacted in the same manner as in phase B of Preparation Example 50 to give the title compound (0.067 g, 91 %).

[0729] <1>H-NMR (CDCl<3>) δ 4.13(2H, s), 3.60(1H, m), 3.50(1H, m), 1.70(1H, m), 1.55(2H, m), 1.20(4H, m), 0.85(1H, m)[0729] <1>H-NMR (CDCl<3>) δ 4.13(2H, s), 3.60(1H, m), 3.50(1H, m), 1.70(1H, m), 1.55(2H, m), 1.20(4H, m), 0.85(1H, m)

[0731] Faza D: etil estar 2-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenoksimetil]-ciklopropankarboksilne kiseline[0731] Phase D: 2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-cyclopropanecarboxylic acid ethyl ester

[0732] Nakon što su etil estar 2-hidroksimetil-ciklopropankarboksilne kiseline (0.067 g, 0.46 mmol) dobijen u fazi C, 2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenol (0.118 g, 0.46 mmol) dobijen u fazi B primera pripreme 2 i trifenilfosfin (0.121 g, 0.46 mmol) rastvoreni u THF-u (5 mL), dodat je diizopropil azokarboksilat, i mešavina je 16 sati mešana na sobnoj temperaturi. Reaktant je koncentrovan pod smanjenim pritiskom i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.084 g, 47 %).[0732] After 2-hydroxymethyl-cyclopropanecarboxylic acid ethyl ester (0.067 g, 0.46 mmol) obtained in phase C, 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.118 g, 0.46 mmol) obtained in phase B of preparation example 2 and triphenylphosphine (0.121 g, 0.46 mmol) dissolved in THF (5 mL), diisopropyl azocarboxylate was added, and the mixture was stirred at room temperature for 16 h. The reactant was concentrated under reduced pressure and purified by column chromatography to give the title compound (0.084 g, 47 %).

[0733] <1>H-NMR (CDCl<3>) δ 7.28(2H, m), 4.11(3H, m), 4.00(1H, m), 1.85(1H, m), 1.60(1H, m), 1.29(12H, s), 1.25(4H, m), 0.85(1H, m)[0733] <1>H-NMR (CDCl<3>) δ 7.28(2H, m), 4.11(3H, m), 4.00(1H, m), 1.85(1H, m), 1.60(1H, m), 1.29(12H, s), 1.25(4H, m), 0.85(1H, m)

[0735] Primer pripreme 53: etil estar 4-[2,5-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenoksi]-buterne kiseline[0735] Preparation example 53: 4-[2,5-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-butyric acid ethyl ester

[0736] Faza A: 4-bromo-2.5-difluoro-fenol[0736] Phase A: 4-bromo-2.5-difluoro-phenol

[0737] 2,5-difluoro-fenol (0.70 g, 2.4 mmol) je rastvoren u hloroformu (18 mL), i bromin (0.431 g, 5.4 mmol) rastvoren u hloroformu (2 mL) je dodat u kapima na 0°C. Mešavina je izreagovana 16 sati, a reakcija završena dodavanjem NaS<2>O<3>vodenog rastvora. Reaktant je razblažen vodom, i ekstrahovan sa EtOAc. Organski sloj je izdvojen i osušen sa MgSO<4>i nastavljeno je sa sledećom fazom.[0737] 2,5-difluoro-phenol (0.70 g, 2.4 mmol) was dissolved in chloroform (18 mL), and bromine (0.431 g, 5.4 mmol) dissolved in chloroform (2 mL) was added dropwise at 0°C. The mixture was reacted for 16 hours, and the reaction was completed by adding NaS<2>O<3> aqueous solution. The reactant was diluted with water, and extracted with EtOAc. The organic layer was separated and dried with MgSO<4> and continued with the next phase.

[0738] <1>H-NMR (CDCl<3>) δ 7.25(1H, m), 6.83(1H, m), 5.23(1H, s)[0738] <1>H-NMR (CDCl<3>) δ 7.25(1H, m), 6.83(1H, m), 5.23(1H, s)

[0740] Faza B: etil estar 4-(4-bromo-2.5-difluoro-fenoksi)-buterne kiseline[0740] Phase B: 4-(4-bromo-2.5-difluoro-phenoxy)-butyric acid ethyl ester

[0741] 4-bromo-2,5-difluoro-fenol (0.865 g, 4.13 mmol) dobijen u fazi A je izreagovan na isti način kao u fazi A primera 38 da bi se dobilo naslovno jedinjenje (1.07 g, 79 %).[0741] 4-Bromo-2,5-difluoro-phenol (0.865 g, 4.13 mmol) obtained in phase A was reacted in the same manner as in phase A of Example 38 to give the title compound (1.07 g, 79 %).

[0742] <1>H-NMR (CDCl<3>) δ 7.24(1H, m), 6.78(1H, m), 4.15(2H, q), 4.05(2H, t), 2.53(2H, t), 2.13(2H, m), 1.25(3H, t)[0742] <1>H-NMR (CDCl<3>) δ 7.24(1H, m), 6.78(1H, m), 4.15(2H, q), 4.05(2H, t), 2.53(2H, t), 2.13(2H, m), 1.25(3H, t)

[0744] Faza C: etil estar 4-[2,5-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenoksil-buterne kiseline[0744] Phase C: 4-[2,5-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxyl-butyric acid ethyl ester

[0745] Etil estar 4-(4-bromo-2,5-difluoro-fenoksi)-buterne kiseline (1.07g, 3.31mmol) dobijen u fazi B, bis(pinakolato)dibor (0.88 g, 3.47 mmol), kalijumacetat (1.30 g, 13.24 mmol) i DPPF (0.092 g, 0.16 mmol) su rastvoreni u 1,4-dioksanu (20 mL), mešavini je dodavan N<2>gas 5 minuta, zatim je dodat PdCl<2>(dppf)-DCM (0.135 g, 0.16 mmol). Reaktant je mešan 16 sati na 80°C, i filtriran upotrebom celite-a, i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.727 g, 59 %).[0745] 4-(4-Bromo-2,5-difluoro-phenoxy)-butyric acid ethyl ester (1.07g, 3.31mmol) obtained in phase B, bis(pinacolato)diboron (0.88g, 3.47mmol), potassium acetate (1.30g, 13.24mmol) and DPPF (0.092g, 0.16mmol) were dissolved in 1,4-dioxane (20 mL), N<2>gas was added to the mixture for 5 min, then PdCl<2>(dppf)-DCM (0.135 g, 0.16 mmol) was added. The reactant was stirred for 16 hours at 80°C, and filtered using celite, and purified by column chromatography to give the title compound (0.727 g, 59 %).

[0746] <1>H-NMR (CDCl<3>) δ 7.37(1H, m), 6.16(1H, m), 4.13(2H, q), 4.06(2H, t), 2.52(2H, t), 2.14(2H, m), 1.30(12H, s), 1.25(3H, t)[0746] <1>H-NMR (CDCl<3>) δ 7.37(1H, m), 6.16(1H, m), 4.13(2H, q), 4.06(2H, t), 2.52(2H, t), 2.14(2H, m), 1.30(12H, s), 1.25(3H, t)

[0748] Primer pripreme 54: etil estar 4-[3,5-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksilbuterne kiseline[0748] Preparation example 54: 4-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxybutyric acid ethyl ester

[0749] 4-bromo-3,5-difluoro-fenol (1.1 g, 5.26 mmol) i etil estar 4-bromo-buterne kiseline (1.03 g, 5.26 mmol) su izreagovani na isti način kao u fazi B primera pripreme 4 da bi se dobio etil estar 4-(4-bromo-3,5-difluoro-fenoksi)-buterne kiseline (0.90 g, 54 %).[0749] 4-bromo-3,5-difluoro-phenol (1.1 g, 5.26 mmol) and 4-bromo-butyric acid ethyl ester (1.03 g, 5.26 mmol) were reacted in the same manner as in phase B of Preparation Example 4 to give 4-(4-bromo-3,5-difluoro-phenoxy)-butyric acid ethyl ester (0.90 g, 54%).

[0750] Zatim su, etil estar 4-(4-bromo-3,5-difluoro-fenoksi)-buterne kiseline (0.37 g, 1.15 mmol) i bis(pinakolato)dibor (0.35 g, 1.37 mmol) izreagovani na isti način kao u fazi A primera pripreme 4 da bi se dobilo naslovno jedinjenje (0.10 g, 24 %).[0750] Next, 4-(4-bromo-3,5-difluoro-phenoxy)-butyric acid ethyl ester (0.37 g, 1.15 mmol) and bis(pinacolato)diboron (0.35 g, 1.37 mmol) were reacted in the same manner as in Step A of Preparation Example 4 to give the title compound (0.10 g, 24%).

[0751] <1>H-NMR (CDCl<3>) δ 6.38(2H, m), 4.15(2H, q), 3.98(2H, t), 2.49(2H, t), 2.11(2H, m), 1.35(12H, s), 1.26(3H, t)[0751] <1>H-NMR (CDCl<3>) δ 6.38(2H, m), 4.15(2H, q), 3.98(2H, t), 2.49(2H, t), 2.11(2H, m), 1.35(12H, s), 1.26(3H, t)

[0753] Primer pripreme 55: 4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenol[0753] Preparation example 55: 4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenol

[0754] 2-ciklopentoksi-3-jodo-piridin (0.52 g, 1.8 mmol) dobijen u primeru pripreme 38 i 2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenol (0.46 g, 1.8 mmol) dobijen u fazi B primera pripreme 2 su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.35 g, 67 %).[0754] 2-Cyclopentoxy-3-iodo-pyridine (0.52 g, 1.8 mmol) obtained in Preparation Example 38 and 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.46 g, 1.8 mmol) obtained in Phase B of Preparation Example 2 were reacted in the same manner as in Preparation Example 13 to give the title compound was obtained (0.35 g, 67 %).

[0755] <1>H-NMR (CDCl<3>) δ 8.14(1H, m), 7.56(1H, m), 7.17(2H, m), 6.93(1H, m), 5.96(1H, bs), 5.51(1H, m), 1.94(2H, m), 1.82(2H, m), 1.74(2H, m), 1.63(2H, m)[0755] <1>H-NMR (CDCl<3>) δ 8.14(1H, m), 7.56(1H, m), 7.17(2H, m), 6.93(1H, m), 5.96(1H, bs), 5.51(1H, m), 1.94(2H, m), 1.82(2H, m), 1.74(2H, m), 1.63(2H, m)

[0757] Primer pripreme 56: 4-[2,6-difluoro-4-(2-fluoro-3-piridil) fenoksi]buterna kiselina[0757] Preparation example 56: 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butyric acid

[0758] Etil 4-[2,6-difluoro-4-(2-fluoro-3-piridil)fenoksi]butanoat (1.7 g, 5.01 mmol) dobijen u primeru pripreme 109 je izreagovan na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (1.5 g, 96 %).[0758] Ethyl 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butanoate (1.7 g, 5.01 mmol) obtained in Preparative Example 109 was reacted in the same manner as in Step B of Example 1 to give the title compound (1.5 g, 96 %).

[0759] <1>H-NMR (CDCl<3>) δ 8.22(1H, m), 7.82(1H, m), 7.29(1H, m), 7.15(2H, m), 4.27(2H, t), 2.68(2H, t), 2.14(2H, m)[0759] <1>H-NMR (CDCl<3>) δ 8.22(1H, m), 7.82(1H, m), 7.29(1H, m), 7.15(2H, m), 4.27(2H, t), 2.68(2H, t), 2.14(2H, m)

[0761] Primer pripreme 57: etil estar 4-[2,6-difluoro-4-(6-formil-piridin-2-il)-fenoksi]-buterna kiselina [0239] 6-bromo-piridin-2-karbaldehid (0.50 g, 2.7 mmol) i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (1.0 g, 2.7 mmol) dobijen u primeru pripreme 2 su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.40 g, 43 %).[0761] Preparation example 57: 4-[2,6-difluoro-4-(6-formyl-pyridin-2-yl)-phenoxy]-butyric acid ethyl ester [0239] 6-bromo-pyridine-2-carbaldehyde (0.50 g, 2.7 mmol) and ethyl ester 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid (1.0 g, 2.7 mmol) obtained in Preparation Example 2 was reacted in the same manner as in Preparation Example 13 to give the title compound (0.40 g, 43 %).

[0762] <1>H-NMR (CDCl<3>) δ 10.1 (1H, s), 7.93(2H, m), 7.86(1H, d), 7.69(2H, m), 4.27(2H, t), 4.16(2H, q), 2.62(2H, t), 2.13(2H, m), 1.28(3H, t)[0762] <1>H-NMR (CDCl<3>) δ 10.1 (1H, s), 7.93(2H, m), 7.86(1H, d), 7.69(2H, m), 4.27(2H, t), 4.16(2H, q), 2.62(2H, t), 2.13(2H, m), 1.28(3H, t)

[0764] Primer pripreme 58: 3-jodo-2-(tetrahidro-piran-4-iloksi)-piridin[0764] Preparation example 58: 3-iodo-2-(tetrahydro-pyran-4-yloxy)-pyridine

[0765] Tetrahidro-piran-4-ol (0.45 g, 4.44 mmol) i 2-fluoro-3-jodo-piridin (0.66 g, 2.96 mmol) su izreagovani na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (0.80 g, 89 %).[0765] Tetrahydro-pyran-4-ol (0.45 g, 4.44 mmol) and 2-fluoro-3-iodo-pyridine (0.66 g, 2.96 mmol) were reacted in the same manner as in Preparation Example 37 to give the title compound (0.80 g, 89 %).

[0766] <1>H-NMR (CDCl<3>) δ 8.07(1H, d), 8.01(1H, d), 6.63(1H, m), 5.30(1H, m), 4.01(2H, m), 3.68(2H, m), 2.04(2H, m), 1.85(2H, m)[0766] <1>H-NMR (CDCl<3>) δ 8.07(1H, d), 8.01(1H, d), 6.63(1H, m), 5.30(1H, m), 4.01(2H, m), 3.68(2H, m), 2.04(2H, m), 1.85(2H, m)

[0767] Primer pripreme 59: 3-jodo-2-(tetrahidro-furan-3-iloksi)-piridin[0767] Preparation example 59: 3-iodo-2-(tetrahydro-furan-3-yloxy)-pyridine

[0768] Tetrahidro-furan-3-ol (0.39 g, 4.44 mmol) i 2-fluoro-3-jodo-piridin (0.66 g, 2.96 mmol) su izreagovani na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (0.68 g, 80 %).[0768] Tetrahydro-furan-3-ol (0.39 g, 4.44 mmol) and 2-fluoro-3-iodo-pyridine (0.66 g, 2.96 mmol) were reacted in the same manner as in Preparation Example 37 to give the title compound (0.68 g, 80%).

[0769] <1>H-NMR (CDCl<3>) δ 8.08(1H, m), 8.03(1H, m), 6.65(1H, m), 5.53(1H, m), 4.12(1H, m), 4.06(1H, m), 3.94(2H, m), 2.23(2H, m)[0769] <1>H-NMR (CDCl<3>) δ 8.08(1H, m), 8.03(1H, m), 6.65(1H, m), 5.53(1H, m), 4.12(1H, m), 4.06(1H, m), 3.94(2H, m), 2.23(2H, m)

[0771] Primer pripreme 60: 1-ciklobutoksi-3-jodo-benzen[0771] Preparation example 60: 1-cyclobutoxy-3-iodo-benzene

[0772] Nakon što je 3-jodofenol (0.5 g, 2.27 mmol) rastvoren u CH<3>CN (5 mL), dodati su Cs<2>CO<3>(2.22 g, 6.81 mmol) i bromociklobutan (0.21 mL, 2.27 mmol). Mešavina je 10 sati mešana na 80-85°C, i reaktant je ohlađen i filtriran upotrebom celite-a. Ostatak je koncentrovan pod smanjenim pritiskom i prečišćen hromatografijom na koloni (eluent: EtOAc/Hex = 1/10) da bi se dobilo naslovno jedinjenje (0.45 g, 72 %).[0772] After 3-iodophenol (0.5 g, 2.27 mmol) was dissolved in CH<3>CN (5 mL), Cs<2>CO<3> (2.22 g, 6.81 mmol) and bromocyclobutane (0.21 mL, 2.27 mmol) were added. The mixture was stirred at 80-85°C for 10 hours, and the reactant was cooled and filtered using celite. The residue was concentrated under reduced pressure and purified by column chromatography (eluent: EtOAc/Hex = 1/10) to give the title compound (0.45 g, 72 %).

[0773] <1>H NMR (400 MHz, CDCl<3>) δ 7.25-7.20(m, 1H), 7.17-7.13(m, 1H), 6.92(t, 1H), 6.77-6.72(m, 1H), 4.59-4.50(m, 1H), 2.44-2.33(m, 2H), 2.19-2.05(m, 2H), 1.88-1.77(m, 1H), 1.70-1.57(m, 1H)[0773] <1>H NMR (400 MHz, CDCl<3>) δ 7.25-7.20(m, 1H), 7.17-7.13(m, 1H), 6.92(t, 1H), 6.77-6.72(m, 1H), 4.59-4.50(m, 1H), 2.44-2.33(m, 2H), 2.19-2.05(m, 2H), 1.88-1.77(m, 1H), 1.70-1.57(m, 1H)

[0775] Primer pripreme 61: 2-ciklobutilmetoksi-3-jodo-piridin[0775] Preparation example 61: 2-cyclobutylmethoxy-3-iodo-pyridine

[0776] Ciklobutil-metanol (0.37 g, 4.31 mmol) i 2-fluoro-3-jodo-piridin (0.60 g, 2.69 mmol) su izreagovani na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (0.75 g, 96 %).[0776] Cyclobutyl-methanol (0.37 g, 4.31 mmol) and 2-fluoro-3-iodo-pyridine (0.60 g, 2.69 mmol) were reacted in the same manner as in Preparation Example 37 to give the title compound (0.75 g, 96 %).

[0777] <1>H-NMR (CDCl<3>) δ 8.08 (1H, m), 8.02(1H, m), 6.63(1H, m), 4.29(2H, d), 2.79(1H, m), 2.12(2H, m), 1.96(4H, m)[0777] <1>H-NMR (CDCl<3>) δ 8.08 (1H, m), 8.02(1H, m), 6.63(1H, m), 4.29(2H, d), 2.79(1H, m), 2.12(2H, m), 1.96(4H, m)

[0779] Primer pripreme 62: 2-ciklopropoksi-3-jodo-piridin[0779] Preparation example 62: 2-cyclopropoxy-3-iodo-pyridine

[0780] Ciklopropanol (0.20 g, 3.43 mmol) i 2-fluoro-3-jodo-piridin (0.51 g, 2.29 mmol) su izreagovani na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (0.30 g, 50 %).[0780] Cyclopropanol (0.20 g, 3.43 mmol) and 2-fluoro-3-iodo-pyridine (0.51 g, 2.29 mmol) were reacted in the same manner as in Preparation Example 37 to give the title compound (0.30 g, 50 %).

[0781] <1>H-NMR (CDCl<3>) δ 8.16(1H, d), 8.01(1H, d), 6.68(1H, m), 4.30(1H, m), 0.82(4H, m)[0781] <1>H-NMR (CDCl<3>) δ 8.16(1H, d), 8.01(1H, d), 6.68(1H, m), 4.30(1H, m), 0.82(4H, m)

[0783] Primer pripreme 63: 2,6-difluoro-4-(2-izopropilsulfanil-piridin-3-il)-fenol[0783] Preparation example 63: 2,6-difluoro-4-(2-isopropylsulfanyl-pyridin-3-yl)-phenol

[0784] Faza A: 3-(3.5-difluoro-4-metoksi-fenil)-2-izopropilsulfanil-piridin[0784] Phase A: 3-(3,5-difluoro-4-methoxy-phenyl)-2-isopropylsulfanyl-pyridine

[0785] 3-hloro-2-izopropilsulfanil-piridin (0.04 g, 0.213 mmol) dobijen u fazi A primera pripreme 33 i 2-(3,5-difluoro-4-metoksi-fenil)-4,4,5,5-tetrametil-[1,3,2]dioksaborolan (0.086 g, 0.139 mmol) dobijen u primeru pripreme 238 su izreagovani na isti način kao u fazi B primera pripreme 33 da bi se dobilo naslovno jedinjenje (0.015 g, 24 %).[0785] 3-chloro-2-isopropylsulfanyl-pyridine (0.04 g, 0.213 mmol) obtained in phase A of preparation example 33 and 2-(3,5-difluoro-4-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.086 g, 0.139 mmol) obtained in preparation example 238 were reacted at the same way as in step B of Preparation Example 33 to give the title compound (0.015 g, 24 %).

[0786] <1>H-NMR (CDCl<3>) δ 8.44(1H, m), 7.33(1H, m), 7.00(3H, m), 4.05(4H, m), 1.37(6H, d)[0786] <1>H-NMR (CDCl<3>) δ 8.44(1H, m), 7.33(1H, m), 7.00(3H, m), 4.05(4H, m), 1.37(6H, d)

[0788] Faza B: 2.6-difluoro-4-(2-izopropilsulfanil-piridin-3-il)-fenol[0788] Phase B: 2,6-difluoro-4-(2-isopropylsulfanyl-pyridin-3-yl)-phenol

[0789] 3-(3,5-difluoro-4-metoksi-fenil)-2-izopropilsulfanil-piridin (0.015 g, 0.05 mmol) dobijen u fazi A je izreagovan na isti način kao u fazi C primera pripreme 33 da bi se dobilo naslovno jedinjenje (0.012 g, 85 %).[0789] 3-(3,5-difluoro-4-methoxy-phenyl)-2-isopropylsulfanyl-pyridine (0.015 g, 0.05 mmol) obtained in phase A was reacted in the same manner as in phase C of Preparation Example 33 to give the title compound (0.012 g, 85 %).

[0790] <1>H-NMR (CDCl<3>) δ 8.44(1H, m), 7.33(1H, m), 7.00(3H, m), 5.25(1H, s), 4.06(1H, m), 1.37(6H, d)[0790] <1>H-NMR (CDCl<3>) δ 8.44(1H, m), 7.33(1H, m), 7.00(3H, m), 5.25(1H, s), 4.06(1H, m), 1.37(6H, d)

[0792] Primer pripreme 64: N-ciklopentil-3-jodo-piridin-2-amin[0792] Preparation example 64: N-cyclopentyl-3-iodo-pyridin-2-amine

[0793] Pošto su 2-fluoro-3-jodo-piridin (0.3 g, 1.34 mmol), ciklopentilamin (0.34 g, 4 mmol) i diizopropil etilamin (0.46 mL, 2.68 mmol) rastvoreni u CH<3>CN (3.3 mL), mešavina je 2 sata mešana na 110°C pomoću mikrotalasa. Reaktant je koncentrovan pod smanjenim pritiskom i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.155 g, 40%).[0793] As 2-fluoro-3-iodo-pyridine (0.3 g, 1.34 mmol), cyclopentylamine (0.34 g, 4 mmol) and diisopropyl ethylamine (0.46 mL, 2.68 mmol) were dissolved in CH<3>CN (3.3 mL), the mixture was stirred for 2 hours at 110°C using a microwave. The reactant was concentrated under reduced pressure and purified by column chromatography to give the title compound (0.155 g, 40%).

[0794] <1>H-NMR (CDCl<3>) δ 8.07 (1H, d), 7.80 (1H, d), 6.28 (1H, m), 4.88 (1H, brs), 4.30 (1H, m), 2.10 (2H, m), 1.75 (2H,m), 1.65 (2H, m), 1.48 (2H, m)[0794] <1>H-NMR (CDCl<3>) δ 8.07 (1H, d), 7.80 (1H, d), 6.28 (1H, m), 4.88 (1H, brs), 4.30 (1H, m), 2.10 (2H, m), 1.75 (2H, m), 1.65 (2H, m), 1.48 (2H, m)

[0796] Primer pripreme 65: 6-hloro-N-(ciklopropilmetil)piridin-2-amin[0796] Preparation example 65: 6-chloro-N-(cyclopropylmethyl)pyridin-2-amine

[0797] 2,6-dihloropiridin (0.15 g, 10 mmol), ciklopropil metanamin (1.3 mL, 15 mmol), (2-bifenil)di-tertbutilfosfin (0.15 g, 0.5 mmol) i natrijum tert - butoksid (1.44 g, 15 mmol) su rastvoreni u toluenu (50 mL), paladijum(II) acetat (0.11 g, 0.05 mmol) je polako dodat, i mešavina je 6 sati mešana na 80°C. Reaktant je koncentrovan pod smanjenim pritiskom i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.21 g, 8.8%).[0797] 2,6-Dichloropyridine (0.15 g, 10 mmol), cyclopropyl methanamine (1.3 mL, 15 mmol), (2-biphenyl)di-tertbutylphosphine (0.15 g, 0.5 mmol) and sodium tert -butoxide (1.44 g, 15 mmol) were dissolved in toluene (50 mL), palladium(II) acetate (0.11 g, 0.05 mmol) was added slowly, and the mixture was stirred at 80°C for 6 hours. The reactant was concentrated under reduced pressure and purified by column chromatography to give the title compound (0.21 g, 8.8%).

[0798] <1>H-NMR (CDCl<3>) δ 7.33 (1H, t), 6.56 (1H, d), 6.24 (1H, d), 3.10 (2H, m), 1.06 (1H, m), 0.54 (2H, m), 0.25 (2H, m)[0798] <1>H-NMR (CDCl<3>) δ 7.33 (1H, t), 6.56 (1H, d), 6.24 (1H, d), 3.10 (2H, m), 1.06 (1H, m), 0.54 (2H, m), 0.25 (2H, m)

[0800] Primer pripreme 66: 3-jodo-N-izopropil-piridin-2-amin[0800] Preparation example 66: 3-iodo-N-isopropyl-pyridin-2-amine

[0801] 2-fluoro-3-jodo-piridin (0.15 g, 0.67 mmol) i propan-2-amin (0.17 mL, 2 mmol) su izreagovani na isti način kao u primeru pripreme 64 da bi se dobilo naslovno jedinjenje (0.047 g, 27%).[0801] 2-Fluoro-3-iodo-pyridine (0.15 g, 0.67 mmol) and propan-2-amine (0.17 mL, 2 mmol) were reacted in the same manner as in Preparation Example 64 to give the title compound (0.047 g, 27%).

[0802] <1>H-NMR (CDCl<3>) δ 8.06 (1H, m), 7.80 (1H, d), 6.28 (1H, m), 4.73 (1H, brs), 4.20 (1H, m), 1.25 (6H, d)[0802] <1>H-NMR (CDCl<3>) δ 8.06 (1H, m), 7.80 (1H, d), 6.28 (1H, m), 4.73 (1H, brs), 4.20 (1H, m), 1.25 (6H, d)

[0804] Primer pripreme 67: N-ciklopropil-3-jodo-piridin-2-amin[0804] Preparation example 67: N-cyclopropyl-3-iodo-pyridin-2-amine

[0805] 2-fluoro-3-jodo-piridin (0.15 g, 0.67 mmol) i ciklopropanamin (0.14 mL, 2 mmol) su izreagovani na isti način kao u primeru pripreme 64 da bi se dobilo naslovno jedinjenje (0.013 g, 8%).[0805] 2-Fluoro-3-iodo-pyridine (0.15 g, 0.67 mmol) and cyclopropanamine (0.14 mL, 2 mmol) were reacted in the same manner as in Preparation Example 64 to give the title compound (0.013 g, 8%).

[0806] <1>H-NMR (CDCl<3>) δ 8.17 (1H, m), 7.82 (1H, m), 6.37 (1H, m), 5.17 (1H, brs), 2.78 (1H, m), 0.86 (2H, m), 0.56 (2H, m)[0806] <1>H-NMR (CDCl<3>) δ 8.17 (1H, m), 7.82 (1H, m), 6.37 (1H, m), 5.17 (1H, brs), 2.78 (1H, m), 0.86 (2H, m), 0.56 (2H, m)

[0808] Primer pripreme 68: tert-butil N-(6-bromo-2-piridil)karbamat[0808] Preparation example 68: tert-butyl N-(6-bromo-2-pyridyl)carbamate

[0809] 6-bromo-piridin-2-ilamin (0.717 g, 4.14 mmol), TEA (0.75 mL, 5.39 mmol) i dimetil aminopiridin (0.1 g, 0.83 mmol) su rastvoreni u DCM-u (6 mL), tert - butoksiugljenikil tert-butil karbonat (1.08 g, 4.96 mmol) rastvoren u DCM-u (1.4 mL) je polako dodat na sobnoj temperaturi. Mešavina je 3 sata mešana na sobnoj temperaturi, i koncentrovana pod smanjenim pritiskom, i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.648 g, 57 %).[0809] 6-Bromo-pyridin-2-ylamine (0.717 g, 4.14 mmol), TEA (0.75 mL, 5.39 mmol) and dimethyl aminopyridine (0.1 g, 0.83 mmol) were dissolved in DCM (6 mL), tert-butoxycarbonate tert-butyl carbonate (1.08 g, 4.96 mmol) was dissolved in DCM. (1.4 mL) was slowly added at room temperature. The mixture was stirred at room temperature for 3 hours, and concentrated under reduced pressure, and purified by column chromatography to give the title compound (0.648 g, 57 %).

[0810] <1>H-NMR (CDCl<3>) δ 7.88 (1H, d), 7.50 (1H, t), 7.20 (1H, brs), 7.12 (1H, d), 1.51 (9H, s)[0810] <1>H-NMR (CDCl<3>) δ 7.88 (1H, d), 7.50 (1H, t), 7.20 (1H, brs), 7.12 (1H, d), 1.51 (9H, s)

[0812] Primer pripreme 69: tert-butil N-(6-bromo-2-piridil)-N-izopropil-karbamat[0812] Preparation example 69: tert-butyl N-(6-bromo-2-pyridyl)-N-isopropyl-carbamate

[0813] Nakon što je tert-butil N-(6-bromo-2-piridil)karbamat (0.2 g, 0.73 mmol) dobijen u primeru pripreme 68 rastvoren u DMF-u (2.5 mL), NaH (60% u mineralnom ulju, 0.048 g, 1.1 mmol) je polako dodat, i mešavina 30 minuta je mešana na sobnoj temperaturi. Dodat je 2-bromopropan (0.14 mL, 1.46 mmol), i mešavina 16 sati je mešana na sobnoj temperaturi. Reaktant je koncentrovan pod smanjenim pritiskom, dodat sa vodenim rastvorom amonijakhlorida a zatim je ekstrahovan sa EtOAc. Organski sloj je izdvojen i osušen sa MgSO<4>, i prečišćen je hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.06 g, 26 %).[0813] After tert-butyl N-(6-bromo-2-pyridyl)carbamate (0.2 g, 0.73 mmol) obtained in Preparative Example 68 was dissolved in DMF (2.5 mL), NaH (60% in mineral oil, 0.048 g, 1.1 mmol) was slowly added, and the mixture was stirred at room temperature for 30 minutes. 2-Bromopropane (0.14 mL, 1.46 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reactant was concentrated under reduced pressure, added with aqueous ammonia solution and then extracted with EtOAc. The organic layer was separated and dried with MgSO<4> , and purified by column chromatography to give the title compound (0.06 g, 26 %).

[0814] <1>H-NMR (CDCl<3>) δ 7.84 (1H, t), 7.27 (1H, d), 7.21 (1H, d), 4.55 (1H, m), 1.44 (9H, s), 1.30 (6H, d)[0814] <1>H-NMR (CDCl<3>) δ 7.84 (1H, t), 7.27 (1H, d), 7.21 (1H, d), 4.55 (1H, m), 1.44 (9H, s), 1.30 (6H, d)

[0816] Primer pripreme 70: N-ciklopentil-2-jodo-anilin[0816] Preparation example 70: N-cyclopentyl-2-iodo-aniline

[0817] Nakon što je 2-jodoanilin (0.39 g, 1.78 mmol) rastvoren u dihloroetanu (6 mL), dodati su ciklopentanon (0.15 g, 1.78 mmol) i sirćetna kiselina (0.11 mL, 1.96 mmol), i mešavina je mešana 16 sati na sobnoj temperaturi. Dodat je natrijum triacetoksiborohidrid (0.56 g, 2.67 mmol), i mešavina je mešana 5 sati. Reaktant je razblažen vodom i ekstrahovan DCM-om. Organski sloj je izdvojen i osušen sa MgSO<4>, i prečišćen je hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.12 g, 23 %).[0817] After 2-iodoaniline (0.39 g, 1.78 mmol) was dissolved in dichloroethane (6 mL), cyclopentanone (0.15 g, 1.78 mmol) and acetic acid (0.11 mL, 1.96 mmol) were added, and the mixture was stirred for 16 hours at room temperature. Sodium triacetoxyborohydride (0.56 g, 2.67 mmol) was added, and the mixture was stirred for 5 hours. The reactant was diluted with water and extracted with DCM. The organic layer was separated and dried with MgSO<4> , and purified by column chromatography to give the title compound (0.12 g, 23 %).

[0818] <1>H-NMR (CDCl<3>) δ 7.64 (1H, d), 7.18 (1H, t), 6.60 (1H, d), 6.40 (1H, t), 4.14 (1H, brs), 3.80 (1H, m), 2.02 (2H, m), 1.76 (2H, m), 1.63 (2H, m), 1.53 (2H, m)[0818] <1>H-NMR (CDCl<3>) δ 7.64 (1H, d), 7.18 (1H, t), 6.60 (1H, d), 6.40 (1H, t), 4.14 (1H, brs), 3.80 (1H, m), 2.02 (2H, m), 1.76 (2H, m), 1.63 (2H, m), 1.53 (2H, m)

[0820] Primer pripreme 71: 3-bromo-N-ciklopentil-anilin[0820] Preparation example 71: 3-bromo-N-cyclopentyl-aniline

[0821] 3-bromoanilin (0.306 g, 1.78 mmol) i ciklopentanon (0.15 g, 1.78 mmol) su izreagovani na isti način kao u primeru pripreme 70 da bi se dobilo naslovno jedinjenje (0.347 g, 81%).[0821] 3-Bromoaniline (0.306 g, 1.78 mmol) and cyclopentanone (0.15 g, 1.78 mmol) were reacted in the same manner as in Preparation Example 70 to give the title compound (0.347 g, 81%).

[0822] <1>H-NMR (CDCl<3>) δ 6.98 (1H, t), 6.77 (1H, d), 6.72 (1H, m), 6.49 (1H, m), 3.77 (2H, m), 2.02 (2H, m) 1.72 (2H, m), 1.62 (2H, m), 1.45 (2H, m)[0822] <1>H-NMR (CDCl<3>) δ 6.98 (1H, t), 6.77 (1H, d), 6.72 (1H, m), 6.49 (1H, m), 3.77 (2H, m), 2.02 (2H, m) 1.72 (2H, m), 1.62 (2H, m), 1.45 (2H, m)

[0824] Primer pripreme 72: 2-jodo-N-propil-anilin[0824] Preparation example 72: 2-iodo-N-propyl-aniline

[0825] 2-jodoanilin (0.5 g, 2.3 mmol) i propanal (0.22 mL, 3.0 mmol) su izreagovani na isti način kao u primeru pripreme 70 da bi se dobilo naslovno jedinjenje (0.39 g, 60%).[0825] 2-Iodoaniline (0.5 g, 2.3 mmol) and propanal (0.22 mL, 3.0 mmol) were reacted in the same manner as in Preparation Example 70 to give the title compound (0.39 g, 60%).

[0826] <1>H-NMR (CDCl<3>) δ 7.65 (1H, d), 7.20 (1H, t), 6.56 (1H, d), 6.42 (1H, t), 4.15 (1H, brs), 3.12 (2H, q), 1.70 (2H, m), 1.03 (3H, t)[0826] <1>H-NMR (CDCl<3>) δ 7.65 (1H, d), 7.20 (1H, t), 6.56 (1H, d), 6.42 (1H, t), 4.15 (1H, brs), 3.12 (2H, q), 1.70 (2H, m), 1.03 (3H, t)

[0827] Primer pripreme 73: N-(ciklopropilmetil)-2-jodo-anilin[0827] Preparation example 73: N-(cyclopropylmethyl)-2-iodo-aniline

[0828] 2-jodoanilin (0.5 g, 2.3 mmol) i ciklopropankarbaldehid (0.2 mL, 2.76 mmol) su izreagovani na isti način kao u primeru pripreme 70 da bi se dobilo naslovno jedinjenje (0.5 g, 80%).[0828] 2-Iodoaniline (0.5 g, 2.3 mmol) and cyclopropanecarbaldehyde (0.2 mL, 2.76 mmol) were reacted in the same manner as in Preparation Example 70 to give the title compound (0.5 g, 80%).

[0829] <1>H-NMR (CDCl<3>) δ 7.66 (1H, d), 7.20 (1H, t), 6.54 (1H, d), 6.43 (1H, t), 4.27 (1H, brs), 3.00 (2H, m), 1.15 (1H, m), 0.60 (2H, m), 0.28 (2H, m)[0829] <1>H-NMR (CDCl<3>) δ 7.66 (1H, d), 7.20 (1H, t), 6.54 (1H, d), 6.43 (1H, t), 4.27 (1H, brs), 3.00 (2H, m), 1.15 (1H, m), 0.60 (2H, m), 0.28 (2H, m)

[0831] Primer pripreme 74: 2-jodo-N-izopropil-anilin[0831] Preparation example 74: 2-iodo-N-isopropyl-aniline

[0832] 2-jodoanilin (0.5 g, 2.3 mmol) i aceton (0.25 mL, 3.42 mmol) su izreagovani na isti način kao u primeru pripreme 70 da bi se dobilo naslovno jedinjenje (0.4 g, 66%).[0832] 2-Iodoaniline (0.5 g, 2.3 mmol) and acetone (0.25 mL, 3.42 mmol) were reacted in the same manner as in Preparation Example 70 to give the title compound (0.4 g, 66%).

[0833] <1>H-NMR (CDCl<3>) δ 7.69 (1H, d), 7.23 (1H, t), 6.60 (1H, d), 6.45 (1H, t), 4.03 (1H, brs), 3.70 (1H, m), 1.31 (6H, d)[0833] <1>H-NMR (CDCl<3>) δ 7.69 (1H, d), 7.23 (1H, t), 6.60 (1H, d), 6.45 (1H, t), 4.03 (1H, brs), 3.70 (1H, m), 1.31 (6H, d)

[0835] Primer pripreme 75: 2-bromo-N-ciklobutil-anilin[0835] Preparation example 75: 2-bromo-N-cyclobutyl-aniline

[0836] Nakon što su 1,2-dibromobenzen (0.3 g, 1.27 mmol), ciklobutilamin (0.22 mL, 2.54 mmol), Cs<2>CO<3>(0.83 g, 2.54 mmol) i 4,5-bis(difenilfosfino)-9,9-dimetilksanten (0.073 mg, 0.13 mmol) rastvoreni u 1,4-dioksanu (12 mL), dodat je Pd<2>(dba)<3>(0.03 g, 0.03 mmol) i mešavina 16 sati je mešana pod refluksom. Reaktant je filtriran upotrebom celite-a i prečišćen je hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.136 g, 47%).[0836] After 1,2-dibromobenzene (0.3 g, 1.27 mmol), cyclobutylamine (0.22 mL, 2.54 mmol), Cs<2>CO<3> (0.83 g, 2.54 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.073 mg, 0.13 mmol) were dissolved in 1,4-dioxane. (12 mL), Pd<2>(dba)<3> (0.03 g, 0.03 mmol) was added and the mixture was stirred under reflux for 16 hours. The reactant was filtered using celite and purified by column chromatography to give the title compound (0.136 g, 47%).

[0837] <1>H-NMR (CDCl<3>) δ 7.39 (1H, d), 7.15 (1H, t), 6.54 (2H, m), 4.42 (1H, brs), 3.92 (1H, m), 2.45 (2H, m), 1.87 (4H, m)[0837] <1>H-NMR (CDCl<3>) δ 7.39 (1H, d), 7.15 (1H, t), 6.54 (2H, m), 4.42 (1H, brs), 3.92 (1H, m), 2.45 (2H, m), 1.87 (4H, m)

[0839] Primer pripreme 76: 3-bromo-N-(ciklopropilmetil)anilin[0839] Preparation example 76: 3-bromo-N-(cyclopropylmethyl)aniline

[0840] 3-bromoanilin (0.5 g, 2.9 mmol) i ciklopropankabaldehid (0.26 mL, 3.48 mmol) su izreagovani na isti način kao u primeru pripreme 70 da bi se dobilo naslovno jedinjenje (0.413 g, 62%).[0840] 3-Bromoaniline (0.5 g, 2.9 mmol) and cyclopropanecarbaldehyde (0.26 mL, 3.48 mmol) were reacted in the same manner as in Preparation Example 70 to give the title compound (0.413 g, 62%).

[0841] <1>H-NMR (CDCl<3>) δ 6.99 (1H, t), 6.79 (1H, d), 6.73 (1H, m), 6.51 (1H, m), 3.86 (1H, brs), 2.93 (2H, d), 1.07 (1H, m), 0.56 (2H, m), 0.24 (2H, m)[0841] <1>H-NMR (CDCl<3>) δ 6.99 (1H, t), 6.79 (1H, d), 6.73 (1H, m), 6.51 (1H, m), 3.86 (1H, brs), 2.93 (2H, d), 1.07 (1H, m), 0.56 (2H, m), 0.24 (2H, m)

[0843] Primer pripreme 77: 3-bromo-N-izopropil-anilin[0843] Preparation example 77: 3-bromo-N-isopropyl-aniline

[0844] 3-bromoanilin (0.5 g, 2.9 mmol) i aceton (0.43 mL, 5.8 mmol) su izreagovani na isti način kao u primeru pripreme 70 da bi se dobilo naslovno jedinjenje (0.6 g, 96%).[0844] 3-Bromoaniline (0.5 g, 2.9 mmol) and acetone (0.43 mL, 5.8 mmol) were reacted in the same manner as in Preparation Example 70 to give the title compound (0.6 g, 96%).

[0845] <1>H-NMR (CDCl<3>) δ 7.00 (1H, t), 6.77 (1H, d), 6.70 (1H, m), 6.46 (1H, m), 3.60 (1H, m), 3.51 (1H, brs), 1.20 (6H, d)[0845] <1>H-NMR (CDCl<3>) δ 7.00 (1H, t), 6.77 (1H, d), 6.70 (1H, m), 6.46 (1H, m), 3.60 (1H, m), 3.51 (1H, brs), 1.20 (6H, d)

[0847] Primer pripreme 78: 1-(3-bromofenil)pirolidin[0847] Preparation example 78: 1-(3-bromophenyl)pyrrolidine

[0848] Nakon što su 1,3-dibromobenzen (1.0 g, 4.24 mmol), pirolidin (0.43 mL, 5.0 mmol), natrijum tertbutoksid (1.14 g, 11.87 mmol) i BINAP (0.2 g, 0.32 mmol) rastvoreni u toluenu (17 mL), dodat je Pd<2>(dba)<3>(0.097 g, 0.1 mmol) i mešavina je mešana pod refluksom 4 sata. Reaktant je filtriran upotrebom celite-a i prečišćen je hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.52 g, 54%).[0848] After 1,3-dibromobenzene (1.0 g, 4.24 mmol), pyrrolidine (0.43 mL, 5.0 mmol), sodium tert-butoxide (1.14 g, 11.87 mmol) and BINAP (0.2 g, 0.32 mmol) were dissolved in toluene (17 mL), Pd<2>(dba)<3> (0.097 g, 0.1 mmol) and the mixture was stirred under reflux for 4 hours. The reactant was filtered using celite and purified by column chromatography to give the title compound (0.52 g, 54%).

[0849] <1>H-NMR (CDCl<3>) δ 7.05 (1H, t), 6.75 (1H, d), 6.67 (1H, m), 6.45 (1H, m), 3.26 (4H, m), 2.00 (4H, m)[0849] <1>H-NMR (CDCl<3>) δ 7.05 (1H, t), 6.75 (1H, d), 6.67 (1H, m), 6.45 (1H, m), 3.26 (4H, m), 2.00 (4H, m)

[0851] Primer pripreme 79: 3-bromo-N-propil-anilin[0851] Preparation example 79: 3-bromo-N-propyl-aniline

[0852] 3-bromoanilin (1.45 g, 8.42 mmol) i propanal (0.49 g, 8.42 mmol) su izreagovani na isti način kao u primeru pripreme 70 da bi se dobilo naslovno jedinjenje (0.22 g, 12%).[0852] 3-Bromoaniline (1.45 g, 8.42 mmol) and propanal (0.49 g, 8.42 mmol) were reacted in the same manner as in Preparation Example 70 to give the title compound (0.22 g, 12%).

[0853] <1>H-NMR (CDCl<3>) δ 6.99 (1H, t), 6.78 (1H, d), 6.72 (1H, m), 6.50 (1H, m), 3.70 (1H, brs), 3.05 (2H, t), 1.66 (2H, m), 1.00 (3H, t)[0853] <1>H-NMR (CDCl<3>) δ 6.99 (1H, t), 6.78 (1H, d), 6.72 (1H, m), 6.50 (1H, m), 3.70 (1H, brs), 3.05 (2H, t), 1.66 (2H, m), 1.00 (3H, t)

[0855] Primer pripreme 80: 3-bromo-N-ciklobutil-anilin[0855] Preparation example 80: 3-bromo-N-cyclobutyl-aniline

[0856] 1,3-dibromobenzen (0.45 mL, 3.7 mmol) i ciklobutilamin (0.53 g, 7.45 mmol) su izreagovani na isti način kao u primeru pripreme 75 da bi se dobilo naslovno jedinjenje (0.028 g, 3%).[0856] 1,3-Dibromobenzene (0.45 mL, 3.7 mmol) and cyclobutylamine (0.53 g, 7.45 mmol) were reacted in the same manner as in Preparation Example 75 to give the title compound (0.028 g, 3%).

[0857] <1>H-NMR (CDCl<3>) δ 7.00 (1H, t), 6.79 (1H, d), 6.66 (1H, m), 6.45 (1H, m), 3.87 (2H, m), 2.42 (2H, m), 1.81 (4H, m)[0857] <1>H-NMR (CDCl<3>) δ 7.00 (1H, t), 6.79 (1H, d), 6.66 (1H, m), 6.45 (1H, m), 3.87 (2H, m), 2.42 (2H, m), 1.81 (4H, m)

[0859] Primer pripreme 81: 2-bromo-4-hloro-N-ciklopentil-anilin[0859] Preparation example 81: 2-bromo-4-chloro-N-cyclopentyl-aniline

[0860] 2-bromo-4-hloroanilin (0.508 g, 2.46 mmol) i ciklopentanon (0.207 g, 2.46 mmol) su izreagovani na isti način kao u primeru pripreme 70 da bi se dobilo naslovno jedinjenje (0.083 g, 12%).[0860] 2-Bromo-4-chloroaniline (0.508 g, 2.46 mmol) and cyclopentanone (0.207 g, 2.46 mmol) were reacted in the same manner as in Preparation Example 70 to give the title compound (0.083 g, 12%).

[0861] <1>H-NMR (CDCl<3>) δ 7.39 (1H, m), 7.12 (1H, m), 6.57 (1H, m), 4.25 (1H, brs), 3.76 (1H, m), 2.03 (2H, m), 1.76 (2H, m), 1.63 (2H, m), 1.50 (2H, m)[0861] <1>H-NMR (CDCl<3>) δ 7.39 (1H, m), 7.12 (1H, m), 6.57 (1H, m), 4.25 (1H, brs), 3.76 (1H, m), 2.03 (2H, m), 1.76 (2H, m), 1.63 (2H, m), 1.50 (2H, m)

[0863] Primer pripreme 82: N-ciklopentil-f-fluoro-2-jodo-anilin[0863] Preparation example 82: N-cyclopentyl-f-fluoro-2-iodo-aniline

[0864] f-fluoro-2-jodo-anilin (2.0 g, 18 mmol) i ciklopentanon (0.195 g, 2.32 mmol) su izreagovani na isti način kao u primeru pripreme 70 da bi se dobilo naslovno jedinjenje (0.19 g, 27%).[0864] f-Fluoro-2-iodo-aniline (2.0 g, 18 mmol) and cyclopentanone (0.195 g, 2.32 mmol) were reacted in the same manner as in Preparation Example 70 to give the title compound (0.19 g, 27%).

[0865] <1>H-NMR (CDCl<3>) δ 7.40 (1H, m), 6.95 (1H, m), 6.52 (1H, m), 3.93 (1H, brs), 3.75 (1H, m), 2.03 (2H, m), 1.76 (2H, m), 1.64 (2H, m), 1.51 (2H, m)[0865] <1>H-NMR (CDCl<3>) δ 7.40 (1H, m), 6.95 (1H, m), 6.52 (1H, m), 3.93 (1H, brs), 3.75 (1H, m), 2.03 (2H, m), 1.76 (2H, m), 1.64 (2H, m), 1.51 (2H, m)

[0867] Primer pripreme 83: ciklopenten-1-il trifluorometansulfonat[0867] Preparation example 83: cyclopenten-1-yl trifluoromethanesulfonate

[0868] Ciklopentanon (0.3 g, 3.6 mmol) je rastvoren u THF-u (10 mL), i mešavina je ohlađena do -78°C. Litijum bis(trimetilsilil)amid (1.0M u THF-u, 3.3 mL, 3.3 mmol) je polako dodat, i mešavina je mešana 50 minuta. N-fenil-bis(trifluorometansulfonimid) (1.17 g, 3.27 mmol) je polako dodat, i mešavina je mešana 16 sati. Reaktant je dodat sa vodenim rastvorom amonijakhlorida a zatim je ekstrahovana sa Et<2>O.[0868] Cyclopentanone (0.3 g, 3.6 mmol) was dissolved in THF (10 mL), and the mixture was cooled to -78°C. Lithium bis(trimethylsilyl)amide (1.0M in THF, 3.3 mL, 3.3 mmol) was slowly added, and the mixture was stirred for 50 min. N-phenyl-bis(trifluoromethanesulfonimide) (1.17 g, 3.27 mmol) was added slowly, and the mixture was stirred for 16 hours. The reactant was added with an aqueous solution of ammonia chloride and then extracted with Et<2>O.

[0869] Organski sloj je izdvojen i osušen sa MgSO<4>, i prečišćen je hromatografijom na koloni, i koncentrovan je pod smanjenim pritiskom na 20°C da bi se dobilo naslovno jedinjenje (0.196 g, 27%).[0869] The organic layer was separated and dried with MgSO<4> , and was purified by column chromatography, and concentrated under reduced pressure at 20°C to give the title compound (0.196 g, 27%).

[0870] <1>H-NMR (CDCl<3>) δ 5.63 (1H, m), 2.57 (2H,m), 2.42 (2H, m), 2.03 (2H, m)[0870] <1>H-NMR (CDCl<3>) δ 5.63 (1H, m), 2.57 (2H, m), 2.42 (2H, m), 2.03 (2H, m)

[0872] Primer pripreme 84: 1-(ciklopenten-1-il)-3-nitro-benzen[0872] Preparation example 84: 1-(cyclopenten-1-yl)-3-nitro-benzene

[0873] Nakon što su ciklopenten-1-il trifluorometansulfonat (0.525 g, 2.43 mmol) dobijen u primeru pripreme 83 i (3-nitrofenil)borna kiselina (0.81 g, 4.86 mmol) dodati sa IN NaOH vodenim rastvorom (7.29 mL, 7.29mmol) i 1,4-dioksanom (24 mL), mešavini je dodavan N<2>gas 5 minuta, zatim su dodati PdCl<2>(dppf)-DCM (0.10 g, 0.12 mmol) i DPPF (0.067 g, 0.12 mmol), i mešavina je mešana pod refluksom 16 sati. Reaktantu je dodata voda a zatim je ekstrahovan sa EtOAc, i osušen sa MgSO<4>. Ostatak je prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.055 g, 12%).[0873] After cyclopenten-1-yl trifluoromethanesulfonate (0.525 g, 2.43 mmol) obtained in Preparation Example 83 and (3-nitrophenyl)boronic acid (0.81 g, 4.86 mmol) were added with 1N aqueous NaOH solution (7.29 mL, 7.29 mmol) and 1,4-dioxane (24 mL), N<2> gas was added to the mixture. 5 min, then PdCl<2>(dppf)-DCM (0.10 g, 0.12 mmol) and DPPF (0.067 g, 0.12 mmol) were added, and the mixture was stirred under reflux for 16 h. Water was added to the reactant and then it was extracted with EtOAc, and dried with MgSO<4>. The residue was purified by column chromatography to give the title compound (0.055 g, 12%).

[0874] <1>H-NMR (CDCl<3>) δ 8.24 (1H, m), 8.04 (1H, m), 7.72 (1H, d), 7.48 (1H, t), 6.35 (1H, m), 2.74 (2H, m), 2.58 (2H, m), 2.07 (2H, m)[0874] <1>H-NMR (CDCl<3>) δ 8.24 (1H, m), 8.04 (1H, m), 7.72 (1H, d), 7.48 (1H, t), 6.35 (1H, m), 2.74 (2H, m), 2.58 (2H, m), 2.07 (2H, m)

[0876] Primer pripreme 85: 3-ciklopentilanilin[0876] Preparation example 85: 3-cyclopentylaniline

[0877] 1-(ciklopenten-1-il)-3-nitro-benzen (0.073 g, 0.39 mmol) dobijen u primeru pripreme 84 je izreagovan na isti način kao u fazi B primera pripreme 50 da bi se dobilo naslovno jedinjenje (0.06 g, 95%).[0877] 1-(Cyclopenten-1-yl)-3-nitro-benzene (0.073 g, 0.39 mmol) obtained in Preparative Example 84 was reacted in the same manner as in Step B of Preparative Example 50 to give the title compound (0.06 g, 95%).

[0878] <1>H-NMR (CDCl<3>) δ 7.05 (1H, t), 6.66 (1H, d), 6.58 (1H, m), 6.52 (1H, m), 3.59 (2H, brs), 2.90 (1H, m), 2.02 (2H, m), 1.78 (2H, m), 1.66 (2H, m), 1.55 (2H, m)[0878] <1>H-NMR (CDCl<3>) δ 7.05 (1H, t), 6.66 (1H, d), 6.58 (1H, m), 6.52 (1H, m), 3.59 (2H, brs), 2.90 (1H, m), 2.02 (2H, m), 1.78 (2H, m), 1.66 (2H, m), 1.55 (2H, m)

[0880] Primer pripreme 86: 1-ciklopentil-3-jodo-benzen[0880] Preparation example 86: 1-cyclopentyl-3-iodo-benzene

[0881] Nakon što je 3-ciklopentilanilin (0.06 g, 0.37 mmol) dobijen u primeru pripreme 85 rastvoren u 6M HCl vodenom rastvoru (1.9 mL), natrijumnitrit (0.5M vodeni rastvor, 1.2 mL, 0.6 mmol) je polako dodat na 0°C. Mešavina je mešana na 0°C 10 minuta, i polako dodata sa kalijumjodidom (1.0M vodeni rastvor, 0.9 mL, 0.9 mmol), a zatim mešavina je mešana 40 minuta. Nakon što je vodeni rastvor natrijumbikarbonata dodat da bi se pH rastvora podesila na 10, reaktant je ekstrahovan sa EtOAc, i organski sloj je osušen sa MgSO<4>da bi se dobilo naslovno jedinjenje (0.07 g, 70%).[0881] After the 3-cyclopentylaniline (0.06 g, 0.37 mmol) obtained in Preparation Example 85 was dissolved in 6M aqueous HCl solution (1.9 mL), sodium nitrite (0.5M aqueous solution, 1.2 mL, 0.6 mmol) was slowly added at 0°C. The mixture was stirred at 0°C for 10 minutes, and potassium iodide (1.0 M aqueous solution, 0.9 mL, 0.9 mmol) was slowly added, and then the mixture was stirred for 40 minutes. After aqueous sodium bicarbonate was added to adjust the pH of the solution to 10, the reactant was extracted with EtOAc, and the organic layer was dried with MgSO4 to give the title compound (0.07 g, 70%).

[0882] <1>H-NMR (CDCl<3>) δ 7.58 (1H, m), 7.50 (1H, d), 7.19 (1H, d), 7.00 (1H, t), 2.92 (1H, m), 2.04 (2H, m), 1.80 (2H, m), 1.68 (2H, m), 1.58 (2H, m)[0882] <1>H-NMR (CDCl<3>) δ 7.58 (1H, m), 7.50 (1H, d), 7.19 (1H, d), 7.00 (1H, t), 2.92 (1H, m), 2.04 (2H, m), 1.80 (2H, m), 1.68 (2H, m), 1.58 (2H, m)

[0884] Primer pripreme 87: 1-bromo-3-(ciklopentilmetil)benzen[0884] Preparation example 87: 1-bromo-3-(cyclopentylmethyl)benzene

[0885] Ciklopentil magnezijum bromid (2.0M u Et<2>O, 2.4 mL, 4.8 mmol) je dodat sa katlitičkim bakar(I)jodidom na 0°C, i mešavina je mešana 30 minuta.1-bromo-3-(bromometil)benzen (1.0 g, 4 mmol) rastvoren u THF-u (10 mL) je polako dodat, i mešavina je mešana 16 sati. Reaktant je dodat sa vodenim rastvorom kalijum dihidrogen fosfata i ekstrahovan sa EtOAc. Organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.116 g, 12%).[0885] Cyclopentyl magnesium bromide (2.0M in Et<2>O, 2.4 mL, 4.8 mmol) was added with catalytic copper(I) iodide at 0°C, and the mixture was stirred for 30 minutes. 1-bromo-3-(bromomethyl)benzene (1.0 g, 4 mmol) dissolved in THF (10 mL) was slowly added, and the mixture was stirred for 16 hours. The reactant was added with aqueous potassium dihydrogen phosphate solution and extracted with EtOAc. The organic layer was dried with MgSO4 and purified by column chromatography to give the title compound (0.116 g, 12%).

[0886] <1>H-NMR (CDCl<3>) δ 7.33 (1H, m), 7.32 (1H, m), 7.12 (1H, t), 7.09 (1H, m), 2.57 (2H, d), 2.06 (1H, m), 1.70 (2H, m), 1.64 (2H, m), 1.53 (2H, m), 1.17 (2H, m)[0886] <1>H-NMR (CDCl<3>) δ 7.33 (1H, m), 7.32 (1H, m), 7.12 (1H, t), 7.09 (1H, m), 2.57 (2H, d), 2.06 (1H, m), 1.70 (2H, m), 1.64 (2H, m), 1.53 (2H, m), 1.17 (2H, m)

[0888] Primer pripreme 88: 1-bromo-2-(ciklopentilmetil)benzen[0888] Preparation example 88: 1-bromo-2-(cyclopentylmethyl)benzene

[0889] 1-bromo-2-(bromometil)benzen (1.0 g, 4 mmol) je izreagovan na isti način kao u primeru pripreme 87 da bi se dobilo naslovno jedinjenje (0.24 g, 25%).[0889] 1-Bromo-2-(bromomethyl)benzene (1.0 g, 4 mmol) was reacted in the same manner as in Preparation Example 87 to give the title compound (0.24 g, 25%).

[0890] <1>H-NMR (CDCl<3>) δ 7.51 (1H, d), 7.20 (2H, m), 7.03 (1H, m), 2.74 (2H, d), 2.20 (1H, m), 1.68 (4H, m), 1.26 (4H, m)[0890] <1>H-NMR (CDCl<3>) δ 7.51 (1H, d), 7.20 (2H, m), 7.03 (1H, m), 2.74 (2H, d), 2.20 (1H, m), 1.68 (4H, m), 1.26 (4H, m)

[0892] Primer pripreme 89: 2-bromo-6-(bromometil)piridin[0892] Preparation example 89: 2-bromo-6-(bromomethyl)pyridine

[0893] Nakon što su (6-bromo-2-piridil)metanol (0.768 g, 4.08 mmol) i trifenilfosfin (1.12 g, 4.28 mmol) rastvoreni u DCM-u (7 mL), dodat je ugljenik tetrabromid (1.48 g, 4.45 mmol) na 0°C, i mešavina je zatim mešana 2 sata. Reaktant je koncentrovan pod smanjenim pritiskom i ostatak je prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.527 g, 51%).[0893] After (6-bromo-2-pyridyl)methanol (0.768 g, 4.08 mmol) and triphenylphosphine (1.12 g, 4.28 mmol) were dissolved in DCM (7 mL), carbon tetrabromide (1.48 g, 4.45 mmol) was added at 0°C, and the mixture was then stirred for 2 hours. The reactant was concentrated under reduced pressure and the residue was purified by column chromatography to give the title compound (0.527 g, 51%).

[0894] <1>H-NMR (CDCl<3>) δ 7.55 (1H, t), 7.42 (2H, m), 4.49 (2H, s)[0894] <1>H-NMR (CDCl<3>) δ 7.55 (1H, t), 7.42 (2H, m), 4.49 (2H, s)

[0896] Primer pripreme 90: 2-bromo-6-(dietoksifosforilmetil)piridin[0896] Preparation example 90: 2-bromo-6-(diethoxyphosphorylmethyl)pyridine

[0897] Nakon što su 2-bromo-6-(bromometil)piridin (0.527 g, 2.1 mmol) dobijen u primeru pripreme 89 i trietilfosfit(0.36mL, 2.1 mmol) rastvoreni u toluenu (4 mL), mešavina je mešana pod refluksom 5 dana, a zatim koncentrovana pod smanjenim pritiskom da bi se dobilo naslovno jedinjenje(0.718 g, 99%).[0897] After 2-bromo-6-(bromomethyl)pyridine (0.527 g, 2.1 mmol) obtained in Preparation Example 89 and triethylphosphite (0.36 mL, 2.1 mmol) were dissolved in toluene (4 mL), the mixture was stirred under reflux for 5 days and then concentrated under reduced pressure to give the title compound (0.718 g, 99%).

[0898] <1>H-NMR (CDCl<3>) δ 7.50 (1H, t), 7.37 (2H, m), 4.10 (4H, m), 3.38 (2H, d), 1.29 (6H, t)[0898] <1>H-NMR (CDCl<3>) δ 7.50 (1H, t), 7.37 (2H, m), 4.10 (4H, m), 3.38 (2H, d), 1.29 (6H, t)

[0900] Primer pripreme 91: 2-bromo-6-(ciklopentilidenmetil)piridin[0900] Preparation example 91: 2-bromo-6-(cyclopentylidenemethyl)pyridine

[0901] Nakon što su 2-bromo-6-(dietoksifosforilmetil)piridin (0.24 g, 0.7 mmol) dobijen u primeru pripreme 90 i ciklopentanon (0.058 mg, 0.7 mmol) rastvoreni u THF-u (3.5 mL), litijum bis(trimetilsilil)amid (1.0M u THF-u, 0.84 mL, 0.84 mmol) je polako dodat, i mešavina je mešana 4 sata. Reaktantu je dodata voda a zatim je ekstrahovan sa EtOAc. Organski sloj je izdvojen i osušen sa MgSO<4>, i prečišćen je hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.115 g, 68%).[0901] After 2-bromo-6-(diethoxyphosphorylmethyl)pyridine (0.24 g, 0.7 mmol) obtained in Preparation Example 90 and cyclopentanone (0.058 mg, 0.7 mmol) were dissolved in THF (3.5 mL), lithium bis(trimethylsilyl)amide (1.0 M in THF, 0.84 mL, 0.84 mmol) was slowly added, and the mixture was mixed for 4 hours. Water was added to the reactant and then extracted with EtOAc. The organic layer was separated and dried with MgSO4, and purified by column chromatography to give the title compound (0.115 g, 68%).

[0902] <1>H-NMR (CDCl<3>) δ 7.43 (1H, t), 7.19 (1H, d), 7.12 (1H, d), 6.40 (1H, m), 2.73 (2H, m), 2.52 (2H, m), 1.80 (2H, m), 1.68 (2H, m)[0902] <1>H-NMR (CDCl<3>) δ 7.43 (1H, t), 7.19 (1H, d), 7.12 (1H, d), 6.40 (1H, m), 2.73 (2H, m), 2.52 (2H, m), 1.80 (2H, m), 1.68 (2H, m)

[0903] Primer pripreme 92: 1-bromo-2-(ciklobutilmetil)benzen[0903] Preparation example 92: 1-bromo-2-(cyclobutylmethyl)benzene

[0904] 1-bromo-2-(bromometil)benzen (0.4 g, 1.6 mmol) i Ciklobutil magnezijum bromid (1.0M u THF-u) su izreagovani na isti način kao u primeru pripreme 87 da bi se dobilo naslovno jedinjenje (0.06 g, 17%).[0904] 1-Bromo-2-(bromomethyl)benzene (0.4 g, 1.6 mmol) and cyclobutyl magnesium bromide (1.0 M in THF) were reacted in the same manner as in Preparation Example 87 to give the title compound (0.06 g, 17%).

[0905] <1>H-NMR (CDCl<3>) δ 7.50 (1H, d), 7.20 (1H, t), 7.16 (1H, m), 7.03 (1H, m), 2.83 (2H, d), 2.67 (1H, m), 2.05 (2H, m), 1.85 (2H, m), 1.75 (2H, m)[0905] <1>H-NMR (CDCl<3>) δ 7.50 (1H, d), 7.20 (1H, t), 7.16 (1H, m), 7.03 (1H, m), 2.83 (2H, d), 2.67 (1H, m), 2.05 (2H, m), 1.85 (2H, m), 1.75 (2H, m)

[0906] Primer pripreme 93: 1-bromo-3-(ciklobutilmetil)benzen[0906] Preparation example 93: 1-bromo-3-(cyclobutylmethyl)benzene

[0907] 1-bromo-3-(bromometil)benzen (0.4 g, 1.6 mmol) i ciklobutil magnezijum bromid (1.0M u THF-u) su izreagovani na isti način kao u primeru pripreme 87 da bi se dobilo naslovno jedinjenje (0.03g, 8%).[0907] 1-Bromo-3-(bromomethyl)benzene (0.4 g, 1.6 mmol) and cyclobutyl magnesium bromide (1.0 M in THF) were reacted in the same manner as in Preparation Example 87 to give the title compound (0.03 g, 8%).

[0908] <1>H-NMR (CDCl<3>) δ 7.28 (2H, m), 7.12 (1H, t), 7.05 (1H, m), 2.66 (2H, d), 2.55 (1H, m), 2.03 (2H, m), 1.83 (2H, m), 1.71 (2H, m)[0908] <1>H-NMR (CDCl<3>) δ 7.28 (2H, m), 7.12 (1H, t), 7.05 (1H, m), 2.66 (2H, d), 2.55 (1H, m), 2.03 (2H, m), 1.83 (2H, m), 1.71 (2H, m)

[0910] Primer pripreme 94: 2-bromo-6-(ciklobutilidenmetil)piridin[0910] Preparation example 94: 2-bromo-6-(cyclobutylidenemethyl)pyridine

[0911] 2-bromo-6-(dietoksifosforilmetil)piridin (0.225 g, 0.73 mmol) dobijen u primeru pripreme 90 i ciklobutanon (0.051 g, 0.73 mmol) su izreagovani na isti način kao u primeru pripreme 91 da bi se dobilo naslovno jedinjenje (0.1 g, 61%).[0911] 2-Bromo-6-(diethoxyphosphorylmethyl)pyridine (0.225 g, 0.73 mmol) obtained in Preparation Example 90 and cyclobutanone (0.051 g, 0.73 mmol) were reacted in the same manner as in Preparation Example 91 to give the title compound (0.1 g, 61%).

[0912] <1>H-NMR (CDCl<3>) δ 7.42 (1H, t), 7.19 (1H, d), 7.04 (1H, d), 6.18 (1H, m), 3.13 (2H, m), 2.92 (2H, m), 2.13 (2H, m)[0912] <1>H-NMR (CDCl<3>) δ 7.42 (1H, t), 7.19 (1H, d), 7.04 (1H, d), 6.18 (1H, m), 3.13 (2H, m), 2.92 (2H, m), 2.13 (2H, m)

[0914] Primer pripreme 95: 1-(ciklopenten-1-il)-2-nitro-benzen[0914] Preparation example 95: 1-(cyclopenten-1-yl)-2-nitro-benzene

[0915] Ciklopenten-1-il trifluorometansulfonat (0.196 g, 0.9 mmol) dobijen u primeru pripreme 83 i (2-nitrofenil)borna kiselina (0.226 g, 1.36 mmol) su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.085 g, 50%).[0915] Cyclopenten-1-yl trifluoromethanesulfonate (0.196 g, 0.9 mmol) obtained in Preparation Example 83 and (2-nitrophenyl)boric acid (0.226 g, 1.36 mmol) were reacted in the same manner as in Preparation Example 13 to give the title compound (0.085 g, 50%).

[0916] <1>H-NMR (CDCl<3>) δ 7.74 (1H, d), 7.54 (1H, t), 7.35 (2H, m), 5.84 (1H, m), 2.58 (2H, m), 2.50 (2H, m), 2.02 (2H, m)[0916] <1>H-NMR (CDCl<3>) δ 7.74 (1H, d), 7.54 (1H, t), 7.35 (2H, m), 5.84 (1H, m), 2.58 (2H, m), 2.50 (2H, m), 2.02 (2H, m)

[0918] Primer pripreme 96: 2-ciklopentilanilin[0918] Preparation example 96: 2-cyclopentylaniline

[0919] 1-(ciklopenten-1-il)-2-nitro-benzen (0.085 g, 0.45 mmol) dobijen u primeru pripreme 95 je izreagovan na isti način kao u primeru pripreme 85 da bi se dobilo naslovno jedinjenje (0.061 g, 84%).[0919] 1-(Cyclopenten-1-yl)-2-nitro-benzene (0.085 g, 0.45 mmol) obtained in Preparative Example 95 was reacted in the same manner as in Preparative Example 85 to give the title compound (0.061 g, 84%).

[0920] <1>H-NMR (CDCl<3>) δ 7.13 (1H, d), 7.01 (1H, t), 6.75 (1H, t), 6.68 (1H, d), 3.66 (2H, brs), 2.98 (1H, m), 2.04 (2H, m), 1.80 (2H, m), 1.69 (4H, m)[0920] <1>H-NMR (CDCl<3>) δ 7.13 (1H, d), 7.01 (1H, t), 6.75 (1H, t), 6.68 (1H, d), 3.66 (2H, brs), 2.98 (1H, m), 2.04 (2H, m), 1.80 (2H, m), 1.69 (4H, m)

[0922] Primer pripreme 97: 1-ciklopentil-2-jodo-benzen[0922] Preparation example 97: 1-cyclopentyl-2-iodo-benzene

[0923] 2-ciklopentilanilin (0.061 g, 0.38 mmol) dobijen u primeru pripreme 96 je izreagovan na isti način kao u primeru pripreme 85 da bi se dobilo naslovno jedinjenje (0.067 g, 65%).[0923] 2-Cyclopentylaniline (0.061 g, 0.38 mmol) obtained in Preparative Example 96 was reacted in the same manner as in Preparative Example 85 to give the title compound (0.067 g, 65%).

[0924] <1>H-NMR (CDCl<3>) δ 7.91 (1H, m), 7.27 (2H, m), 6.87 (1H, m), 3.24 (1H, m), 2.12 (2H, m), 1.82 (2H, m), 1.72 (2H, m), 1.53 (2H, m)[0924] <1>H-NMR (CDCl<3>) δ 7.91 (1H, m), 7.27 (2H, m), 6.87 (1H, m), 3.24 (1H, m), 2.12 (2H, m), 1.82 (2H, m), 1.72 (2H, m), 1.53 (2H, m)

[0926] Primer pripreme 98: 2-bromo-6-ciklopentil-piridin[0926] Preparation example 98: 2-bromo-6-cyclopentyl-pyridine

[0927] Nakon što su 2,6-dibromopiridin (0.41 g, 1.73 mmol), bakar(I) jodid (0.078 g, 0.41 mmol) i PdCl<2>(dppf)-DCM (0.167 g, 0.20 mmol) rastvoreni u THF-u (3.5 mL), mešavini je dodavan N<2>gas 5 minuta. Reaktant je polako dodat sa ciklopentilcink bromidom (0.5M u THF-u, 4.1 mL, 2.05 mmol), i mešavina je 16 sati mešana na sobnoj temperaturi. Reaktant je dodat sa Hex-om i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.175 g, 44%).[0927] After 2,6-dibromopyridine (0.41 g, 1.73 mmol), copper(I) iodide (0.078 g, 0.41 mmol) and PdCl<2>(dppf)-DCM (0.167 g, 0.20 mmol) were dissolved in THF (3.5 mL), N<2> gas was added to the mixture for 5 minutes. The reactant was slowly added with cyclopentylzinc bromide (0.5M in THF, 4.1 mL, 2.05 mmol), and the mixture was stirred at room temperature for 16 hours. The reactant was added with Hex and purified by column chromatography to give the title compound (0.175 g, 44%).

[0928] <1>H-NMR (CDCl<3>) δ 7.42 (1H, t), 7.27 (1H, d), 7.12 (1H, d), 3.14 (1H, m), 2.07 (2H, m), 1.79 (6H, m)[0928] <1>H-NMR (CDCl<3>) δ 7.42 (1H, t), 7.27 (1H, d), 7.12 (1H, d), 3.14 (1H, m), 2.07 (2H, m), 1.79 (6H, m)

[0930] Primer pripreme 99: 3-benziloksi-2-metil-piridin[0930] Preparation example 99: 3-benzyloxy-2-methyl-pyridine

[0931] Nakon što je 2-metilpiridin-3-ol (1.25 g, 11 mmol) dodat sa CH<3>CN (32 mL) i tetrabutilamonijak hidroksidom (40 mas.% vodeni rastvor, 2.97 g, 11 mmol), mešavina je mešana na sobnoj temperaturi 30 minuta. Reaktant je koncentrovan pod smanjenim pritiskom, i dodat sa bromometilbenzenom (1.37 mL, 11 mmol) i CH<3>CN (63 mL), i mešavina je mešana pod refluksom 4 sata. Reaktant je koncentrovan pod smanjenim pritiskom i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (1.94 g, 88%).[0931] After 2-methylpyridin-3-ol (1.25 g, 11 mmol) was added with CH<3>CN (32 mL) and tetrabutylammonia hydroxide (40 wt.% aqueous solution, 2.97 g, 11 mmol), the mixture was stirred at room temperature for 30 minutes. The reactant was concentrated under reduced pressure, and bromomethylbenzene (1.37 mL, 11 mmol) and CH<3>CN (63 mL) were added, and the mixture was stirred under reflux for 4 hours. The reactant was concentrated under reduced pressure and purified by column chromatography to give the title compound (1.94 g, 88%).

[0932] <1>H-NMR (CDCl<3>) δ 8.08 (1H, m), 7.41 (4H, m), 7.35 (1H, m), 7.11 (1H, d), 7.07 (1H, m), 5.09 (2H, s), 2.53 (3H, s)[0932] <1>H-NMR (CDCl<3>) δ 8.08 (1H, m), 7.41 (4H, m), 7.35 (1H, m), 7.11 (1H, d), 7.07 (1H, m), 5.09 (2H, s), 2.53 (3H, s)

[0934] Primer pripreme 100: 3-benziloksipiridin -2-karbaldehid[0934] Preparation example 100: 3-benzyloxypyridine-2-carbaldehyde

[0935] Nakon što je 3-benziloksi-2-metil-piridin (0.36 g, 1.8 mmol) dobijen u primeru pripreme 99 rastvoren u 1,4-dioksanu (30 mL), dodat je selenijumdioksid (0.4 g, 3.6 mmol), i mešavina je mešana pod refluksom 4 dana. Reaktant je dodat sa vodenim rastvorom natrijumbikarbonata a zatim je ekstrahovan sa EtOAc. Organski sloj je osušen sa MgSO<4>, i prečišćen je hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.29 g, 75%).[0935] After the 3-benzyloxy-2-methyl-pyridine (0.36 g, 1.8 mmol) obtained in Preparation Example 99 was dissolved in 1,4-dioxane (30 mL), selenium dioxide (0.4 g, 3.6 mmol) was added, and the mixture was stirred under reflux for 4 days. The reactant was added with aqueous sodium bicarbonate and then extracted with EtOAc. The organic layer was dried with MgSO4, and purified by column chromatography to give the title compound (0.29 g, 75%).

[0936] <1>H-NMR (CDCl<3>) δ 10.44 (1H, s), 8.41 (1H, m), 7.40 (7H, m), 5.26 (2H, s)[0936] <1>H-NMR (CDCl<3>) δ 10.44 (1H, s), 8.41 (1H, m), 7.40 (7H, m), 5.26 (2H, s)

[0938] Primer pripreme 101: 3-benziloksi-2-(2-metilprop-1-enil)piridin[0938] Preparation example 101: 3-benzyloxy-2-(2-methylprop-1-enyl)pyridine

[0939] Izopropiltrifenilfosfonijum jodid (0.7 g, 1.6 mmol) je dodat sa THF-om (10 mL), i ohlađen do 0°C. Nakon što je litijum bis(trimetilsilil)amid (1.0M u THF-u, 1.6 mL, 1.6 mmol) polako dodat, mešavina je mešana 10 minuta, i polako je dodat 3-benziloksipiridin-2-karbaldehid (0.29 g, 1.35 mmol) dobijen u primeru pripreme 100 rastvoren u THF-u (5 mL). Mešavina je 2 sata mešana na sobnoj temperaturi, dodata sa vodenim rastvorom amonijakhlorida, a zatim je ekstrahovana sa EtOAc. Organski sloj je osušen sa MgSO<4>, i prečišćen je hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.03g, 9%).[0939] Isopropyltriphenylphosphonium iodide (0.7 g, 1.6 mmol) was added with THF (10 mL), and cooled to 0°C. After lithium bis(trimethylsilyl)amide (1.0M in THF, 1.6 mL, 1.6 mmol) was slowly added, the mixture was stirred for 10 minutes, and 3-benzyloxypyridine-2-carbaldehyde (0.29 g, 1.35 mmol) obtained in Preparation Example 100 dissolved in THF (5 mL) was slowly added. The mixture was stirred at room temperature for 2 hours, added with aqueous ammonia solution, and then extracted with EtOAc. The organic layer was dried with MgSO4, and purified by column chromatography to give the title compound (0.03g, 9%).

[0940] <1>H-NMR (CDCl<3>) δ 8.19 (1H, m), 7.37 (5H, m), 7.14 (1H, d), 7.02 (1H, m), 6.57 (1H, s), 5.09 (2H, s), 2.08 (3H, s), 1.97 (3H, s)[0940] <1>H-NMR (CDCl<3>) δ 8.19 (1H, m), 7.37 (5H, m), 7.14 (1H, d), 7.02 (1H, m), 6.57 (1H, s), 5.09 (2H, s), 2.08 (3H, s), 1.97 (3H, s)

[0942] Primer pripreme 102: 2-izobutilpiridin-3-ol[0942] Preparation example 102: 2-isobutylpyridin-3-ol

[0943] 3-benziloksi-2-(2-metilprop-1-enil) piridin (0.03 g, 0.12 mmol) dobijen u primeru pripreme 101 je izreagovan na isti način kao u fazi B primera pripreme 50 da bi se dobilo naslovno jedinjenje (0.023 g, 99%).[0943] 3-Benzyloxy-2-(2-methylprop-1-enyl)pyridine (0.03 g, 0.12 mmol) obtained in Preparative Example 101 was reacted in the same manner as in Step B of Preparative Example 50 to give the title compound (0.023 g, 99%).

[0944] <1>H-NMR (CDCl<3>) δ 8.00 (1H, m), 7.95 (1H, m), 7.34 (1H, m), 2.90 (2H, d), 2.54 (1H, m), 0.94 (6H, d)[0944] <1>H-NMR (CDCl<3>) δ 8.00 (1H, m), 7.95 (1H, m), 7.34 (1H, m), 2.90 (2H, d), 2.54 (1H, m), 0.94 (6H, d)

[0946] Primer pripreme 103: (2-izobutil-3-piridil) trifluorometan sulfonat[0946] Preparation example 103: (2-isobutyl-3-pyridyl) trifluoromethane sulfonate

[0947] 2-izobutilpiridin-3-ol (0.023 g, 0.15 mmol) dobijen u primeru pripreme 102 je dodat sa DCM-om (0.8 mL), TEA-om (0.023 mL, 0.17 mmol) i N-fenil-bis(trifluorometansulfonimid) (0.06 g, 0.17 mmol), i mešavina je mešana na sobnoj temperaturi 16 sati. Reaktantu je dodata voda, i ekstrahovan sa DCM-om, a zatim je prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.017 g, 40%).[0947] 2-Isobutylpyridin-3-ol (0.023 g, 0.15 mmol) obtained in Preparation Example 102 was added with DCM (0.8 mL), TEA (0.023 mL, 0.17 mmol) and N-phenyl-bis(trifluoromethanesulfonimide) (0.06 g, 0.17 mmol), and the mixture was stirred at room temperature for 16 hours. Water was added to the reactant, and extracted with DCM, then purified by column chromatography to give the title compound (0.017 g, 40%).

[0948] <1>H-NMR (CDCl<3>) δ 8.57 (1H, m), 7.58 (1H, m), 7.25 (1H, m), 2.79 (2H, d), 2.22 (1H, m), 0.95 (6H, d)[0948] <1>H-NMR (CDCl<3>) δ 8.57 (1H, m), 7.58 (1H, m), 7.25 (1H, m), 2.79 (2H, d), 2.22 (1H, m), 0.95 (6H, d)

[0950] Primer pripreme 104: 3-benziloksi-2-bromo-piridin[0950] Preparation example 104: 3-benzyloxy-2-bromo-pyridine

[0951] 2-bromo-3-piridol (10 g, 57 mmol) i bromometilbenzen (7.2 mL, 60 mmol) su izreagovani na isti način kao u primeru pripreme 8 da bi se dobilo naslovno jedinjenje (15 g, 99%).[0951] 2-Bromo-3-pyridol (10 g, 57 mmol) and bromomethylbenzene (7.2 mL, 60 mmol) were reacted in the same manner as in Preparation Example 8 to give the title compound (15 g, 99%).

[0952] <1>H-NMR (CDCl<3>) δ 8.00 (1H, m), 7.44 (2H, m), 7.40 (2H, m), 7.32 (1H, m), 7.18 (2H, m), 5.19 (2H, s)[0952] <1>H-NMR (CDCl<3>) δ 8.00 (1H, m), 7.44 (2H, m), 7.40 (2H, m), 7.32 (1H, m), 7.18 (2H, m), 5.19 (2H, s)

[0954] Primer pripreme 105: 3-benziloksi-2-ciklopentil-piridin[0954] Preparation example 105: 3-benzyloxy-2-cyclopentyl-pyridine

[0955] 3-benziloksi-2-bromo-piridin (1.32 g, 5 mmol) dobijen u primeru pripreme 104 je dodat sa toluenom (10 mL), paladijum(II) acetatom (0.17 g, 0.75 mmol), i SPhos-om(0.62 g, 1.5 mmol), a zatim ohlađen do 0°C. Reaktant je polako dodat sa ciklopentilcinkbromidom (0.5M u THF-u, 15 mL, 7.5 mmol), i mešan na sobnoj temperaturi 4 sata. Reaktantu je zatim dodat vodeni rastvor amonijakhlorida, i ekstrahovan je sa EtOAc. Organski sloj je osušen sa MgSO<4>, i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.832 g, 65%).[0955] 3-Benzyloxy-2-bromo-pyridine (1.32 g, 5 mmol) obtained in Preparation Example 104 was added with toluene (10 mL), palladium(II) acetate (0.17 g, 0.75 mmol), and SPhos (0.62 g, 1.5 mmol), then cooled to 0°C. The reactant was slowly added with cyclopentylzinc bromide (0.5M in THF, 15 mL, 7.5 mmol), and stirred at room temperature for 4 hours. Aqueous ammonia chloride solution was then added to the reactant, and it was extracted with EtOAc. The organic layer was dried with MgSO4, and purified by column chromatography to give the title compound (0.832 g, 65%).

[0956] <1>H-NMR (CDCl<3>) δ 8.15 (1H, m), 7.42 (4H, m), 7.40 (1H, m), 7.12 (1H, m), 7.05 (1H, m), 5.08 (2H, s), 3.64 (1H, m), 1.99 (2H, m), 1.85 (4H, m), 1.67 (2H, m)[0956] <1>H-NMR (CDCl<3>) δ 8.15 (1H, m), 7.42 (4H, m), 7.40 (1H, m), 7.12 (1H, m), 7.05 (1H, m), 5.08 (2H, s), 3.64 (1H, m), 1.99 (2H, m), 1.85 (4H, m), 1.67 (2H, m)

[0958] Primer pripreme 106: (2-ciklopentil-3-piridil) trifluorometan sulfonat[0958] Preparation example 106: (2-cyclopentyl-3-pyridyl) trifluoromethane sulfonate

[0959] 3-benziloksi-2-ciklopentil-piridin (0.5 g, 2 mmol) dobijen u primeru pripreme 105 je izreagovan na isti način kao u fazi B primera pripreme 50 i primera pripreme 103 redom da bi se dobilo naslovno jedinjenje (0.376 g, 66%).[0959] 3-Benzyloxy-2-cyclopentyl-pyridine (0.5 g, 2 mmol) obtained in Preparative Example 105 was reacted in the same manner as in Step B of Preparative Example 50 and Preparative Example 103 respectively to give the title compound (0.376 g, 66%).

[0960] <1>H-NMR (CDCl<3>) δ 8.58 (1H, m), 7.54 (1H, m), 7.22 (1H, m), 3.49 (1H, m), 2.05 (2H, m), 1.89 (4H, m), 1.72 (2H, m)[0960] <1>H-NMR (CDCl<3>) δ 8.58 (1H, m), 7.54 (1H, m), 7.22 (1H, m), 3.49 (1H, m), 2.05 (2H, m), 1.89 (4H, m), 1.72 (2H, m)

[0962] Primer pripreme 107: 3-benziloksi-2-(ciklopentilidenmetil) piridin[0962] Preparation example 107: 3-benzyloxy-2-(cyclopentylidenemethyl)pyridine

[0963] 3-benziloksipiridin-2-karbaldehid (0.3 g, 1.4 mmol) dobijen u primeru pripreme 100 i ciklopentiltrifenilfosfonijum bromid (0.87 g, 2.11 mmol) su izreagovani na isti način kao u primeru pripreme 101 da bi se dobilo naslovno jedinjenje (0.096 g, 26%).[0963] 3-Benzyloxypyridine-2-carbaldehyde (0.3 g, 1.4 mmol) obtained in Preparation Example 100 and cyclopentyltriphenylphosphonium bromide (0.87 g, 2.11 mmol) were reacted in the same manner as in Preparation Example 101 to give the title compound (0.096 g, 26%).

[0964] <1>H-NMR (CDCl<3>) δ 8.19 (1H, m), 7.42 (4H, m), 7.32 (1H, m), 7.10 (1H, m), 6.99 (1H, m), 6.83 (1H, m), 5.09 (2H, s), 2.84 (2H, m), 2.54 (2H, m), 1.76 (2H, m), 1.68 (2H, m)[0964] <1>H-NMR (CDCl<3>) δ 8.19 (1H, m), 7.42 (4H, m), 7.32 (1H, m), 7.10 (1H, m), 6.99 (1H, m), 6.83 (1H, m), 5.09 (2H, s), 2.84 (2H, m), 2.54 (2H, m), 1.76 (2H, m), 1.68 (2H, m)

[0966] Primer pripreme 108: [2-(ciklopentilmetil)-3-piridil] trifluorometansulfonat[0966] Preparation Example 108: [2-(cyclopentylmethyl)-3-pyridyl] trifluoromethanesulfonate

[0967] 3-benziloksi-2-(ciklopentilidenmetil)piridin (0.096 g, 0.36 mmol) dobijen u primeru pripreme 107 je izreagovan na isti način kao u fazi B primera pripreme 50 i primera pripreme 103 redom da bi se dobilo naslovno jedinjenje (0.04 g, 36%).[0967] 3-Benzyloxy-2-(cyclopentylidenemethyl)pyridine (0.096 g, 0.36 mmol) obtained in Preparative Example 107 was reacted in the same manner as in Step B of Preparative Example 50 and Preparative Example 103 respectively to give the title compound (0.04 g, 36%).

[0968] <1>H-NMR (CDCl<3>) δ 8.56 (1H, m), 7.58 (1H, m), 7.25 (1H, m), 2.92 (2H, d), 2.37 (1H, m), 1.72 (4H, m), 1.56 (2H, m), 1.26 (2H, m)[0968] <1>H-NMR (CDCl<3>) δ 8.56 (1H, m), 7.58 (1H, m), 7.25 (1H, m), 2.92 (2H, d), 2.37 (1H, m), 1.72 (4H, m), 1.56 (2H, m), 1.26 (2H, m)

[0970] Primer pripreme 109: etil 4-[2,6-difluoro-4-(2-fluoro-3-piridil) fenoksi]butanoat[0970] Preparation example 109: ethyl 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butanoate

[0971] 2-fluoro-3-jodo-piridin (0.394 g, 1.77 mmol) i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.72 g, 1.94 mmol) dobijen u primeru pripreme 2 su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.55 g, 92%).[0971] 2-Fluoro-3-iodo-pyridine (0.394 g, 1.77 mmol) and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.72 g, 1.94 mmol) obtained in Preparation Example 2 were reacted in the same manner as in Preparation Example 13 to give the title compound was obtained (0.55 g, 92%).

[0972] <1>H-NMR (CDCl<3>) δ 8.22 (1H, m), 7.83 (1H, m), 7.30 (1H, m), 7.15 (2H, m), 4.25 (2H, t), 4.15 (2H, q), 2.59 (2H, t), 2.10 (2H, m), 1.27 (3H, t)[0972] <1>H-NMR (CDCl<3>) δ 8.22 (1H, m), 7.83 (1H, m), 7.30 (1H, m), 7.15 (2H, m), 4.25 (2H, t), 4.15 (2H, q), 2.59 (2H, t), 2.10 (2H, m), 1.27 (3H, t)

[0974] Primer pripreme 110: 4-(3-jodo-2-piridil)morfolin[0974] Preparation example 110: 4-(3-iodo-2-pyridyl)morpholine

[0975] 2-fluoro-3-jodo-piridin (0.3 g, 1.34 mmol) i morfolin (0.35 g, 4 mmol) su izreagovani na isti način kao u primeru pripreme 64 da bi se dobilo naslovno jedinjenje (0.12 g, 28%).[0975] 2-Fluoro-3-iodo-pyridine (0.3 g, 1.34 mmol) and morpholine (0.35 g, 4 mmol) were reacted in the same manner as in Preparation Example 64 to give the title compound (0.12 g, 28%).

[0976] <1>H-NMR (CDCl<3>) δ 8.27 (1H, m), 8.07 (1H, m), 6.68 (1H, m), 3.88 (4H, m), 3.28 (4H, m)[0976] <1>H-NMR (CDCl<3>) δ 8.27 (1H, m), 8.07 (1H, m), 6.68 (1H, m), 3.88 (4H, m), 3.28 (4H, m)

[0978] Primer pripreme 111: 3-jodo-N-(tetrahidropiran-4-ilmetil)piridin-2-amin[0978] Preparation example 111: 3-iodo-N-(tetrahydropyran-4-ylmethyl)pyridin-2-amine

[0979] 2-fluoro-3-jodo-piridin (0.3 g, 1.34 mmol) i 4-aminometiltetrahidropiran (0.46 g, 4 mmol) su izreagovani na isti način kao u primeru pripreme 64 da bi se dobilo naslovno jedinjenje (0.24 g, 56%).[0979] 2-fluoro-3-iodo-pyridine (0.3 g, 1.34 mmol) and 4-aminomethyltetrahydropyran (0.46 g, 4 mmol) were reacted in the same manner as in Preparation Example 64 to give the title compound (0.24 g, 56%).

[0980] <1>H-NMR (CDCl<3>) δ 8.06 (1H, m), 7.81 (1H, m), 6.32 (1H, m), 5.00 (1H, brs), 4.00 (2H, m), 3.41 (2H, m), 3.36 (2H, m), 1.90 (1H, m), 1.70 (2H, m), 1.38 (2H, m)[0980] <1>H-NMR (CDCl<3>) δ 8.06 (1H, m), 7.81 (1H, m), 6.32 (1H, m), 5.00 (1H, brs), 4.00 (2H, m), 3.41 (2H, m), 3.36 (2H, m), 1.90 (1H, m), 1.70 (2H, m), 1.38 (2H, m)

[0982] Primer pripreme 112: metil (2R)-2-(4-bromo-2,6-difluoro-fenoksi)propanoat[0982] Preparation example 112: methyl (2R)-2-(4-bromo-2,6-difluoro-phenoxy)propanoate

[0983] 4-bromo-2,6-difluoro-fenol (2.57 g, 12.3 mmol) dobijen u fazi A primera pripreme 2 i (S)-metillaktat (1.28 g, 12.3 mmol) su izreagovani na isti način kao u fazi C primera pripreme 27 da bi se dobilo naslovno jedinjenje (3.28 g, 90%).[0983] 4-Bromo-2,6-difluoro-phenol (2.57 g, 12.3 mmol) obtained in Step A of Preparative Example 2 and (S)-methyl lactate (1.28 g, 12.3 mmol) were reacted in the same manner as in Step C of Preparative Example 27 to give the title compound (3.28 g, 90%).

[0984] <1>H-NMR (CDCl<3>) δ 7.08 (2H, m), 4.79 (1H, m), 3.77 (3H, s), 1.62 (3H, d)[0984] <1>H-NMR (CDCl<3>) δ 7.08 (2H, m), 4.79 (1H, m), 3.77 (3H, s), 1.62 (3H, d)

[0986] Primer pripreme 113: (2R)-2-(4-bromo-2,6-difluoro-fenoksi)propan-1-ol[0986] Preparation example 113: (2R)-2-(4-bromo-2,6-difluoro-phenoxy)propan-1-ol

[0987] Metil (2R)-2-(4-bromo-2,6-difluoro-fenoksi)propanoat (3.28 g, 11.1 mmol) dobijen u primeru pripreme 112 je izreagovan na isti način kao u fazi A primera pripreme 30 da bi se dobilo naslovno jedinjenje (2.80 g, 94%).[0987] Methyl (2R)-2-(4-bromo-2,6-difluoro-phenoxy)propanoate (3.28 g, 11.1 mmol) obtained in Preparative Example 112 was reacted in the same manner as in Step A of Preparative Example 30 to give the title compound (2.80 g, 94%).

[0988] <1>H NMR (CDCl<3>) δ 7.10 (2H, m), 4.33 (1H, m), 3.75 (1H, m), 3.70 (1H, m), 2.08 (1H, brs), 1.31 (3H, d)[0988] <1>H NMR (CDCl<3>) δ 7.10 (2H, m), 4.33 (1H, m), 3.75 (1H, m), 3.70 (1H, m), 2.08 (1H, brs), 1.31 (3H, d)

[0990] Primer pripreme 114: (2R)-2-(4-bromo-2,6-difluoro-fenoksi)propanal[0990] Preparation example 114: (2R)-2-(4-bromo-2,6-difluoro-phenoxy)propanal

[0991] DCM (75 mL) je dodat sa oksalilhloridom (1.08 mL, 12.6 mmol), i ohlađen do - 78°C. DMSO (1.93 mL, 27.3 mmol) rastvoren u DCM-u (37 mL) je polako dodat, i mešavina je mešana 2 sata. Mešavina je polako dodata sa (2R)-2-(4-bromo-2,6-difluoro-fenoksi)propan-1-olom (2.80 g, 10.48 mmol) dobijenim u primeru pripreme 113 rastvoren u DCM-u (37 mL) i TEA-u (7.0 mL, 50 mmol) redom. Mešavina je mešana na sobnoj temperaturi 1 sat, i dodata je sa IN HCl vodenim rastvorom, a zatim je ekstrahovana sa DCM-om. Organski sloj je osušen sa MgSO<4>, i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (2.28 g, 58%).[0991] DCM (75 mL) was added with oxalyl chloride (1.08 mL, 12.6 mmol), and cooled to -78°C. DMSO (1.93 mL, 27.3 mmol) dissolved in DCM (37 mL) was slowly added, and the mixture was stirred for 2 hours. The mixture was slowly added with (2R)-2-(4-bromo-2,6-difluoro-phenoxy)propan-1-ol (2.80 g, 10.48 mmol) obtained in Preparative Example 113 dissolved in DCM (37 mL) and TEA (7.0 mL, 50 mmol) respectively. The mixture was stirred at room temperature for 1 hour, and 1N aqueous HCl was added, then extracted with DCM. The organic layer was dried with MgSO4, and purified by column chromatography to give the title compound (2.28 g, 58%).

[0992] <1>H NMR (CDCl<3>) δ 9.85 (1H, s), 7.13 (2H, m), 4.51 (1H, m), 1.48 (3H, d)[0992] <1>H NMR (CDCl<3>) δ 9.85 (1H, s), 7.13 (2H, m), 4.51 (1H, m), 1.48 (3H, d)

[0994] Primer pripreme 115: metil (Z,4R)-4-(4-bromo-2,6-difluoro-fenoksi)pent-2-enoat[0994] Preparation example 115: methyl (Z,4R)-4-(4-bromo-2,6-difluoro-phenoxy)pent-2-enoate

[0995] Bis(2,2,2-trifluoroetil)(metoksikarbonilmetil)fosfonat (1.2 g, 3.77 mmol) je rastvoren u THF-u (30 mL), ohlađen do 0°C, i dodat je sa natrijumjodidom (0.67 g, 4.52 mmol) i 1,8-diazabiciklo[5.4.0]undec-7-enom (0.62 mL, 4.15 mmol) redom.10 minuta kasnije mešavina je ohlađena do -78°C, polako je dodata sa (2R)-2-(4-bromo-2,6-difluoro-fenoksi)propanalom (1.0 g, 3.77 mmol) dobijenim u primeru pripreme 114 rastvorenim u THF-u (8 mL). Reaktant je mešan na 0°C 1 sat, dodat sa vodenim rastvorom amonijakhlorida, a zatim je ekstrahovan sa EtOAc. Organski sloj je osušen sa MgSO<4>, i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.7 g, 58%).[0995] Bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate (1.2 g, 3.77 mmol) was dissolved in THF (30 mL), cooled to 0 °C, and added with sodium iodide (0.67 g, 4.52 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.62 mL, 4.15 mmol) respectively. 10 minutes later the mixture was cooled to -78°C, and (2R)-2-(4-bromo-2,6-difluoro-phenoxy)propanal (1.0 g, 3.77 mmol) obtained in Preparative Example 114 dissolved in THF (8 mL) was added slowly. The reactant was stirred at 0°C for 1 hour, added with aqueous ammonia solution, and then extracted with EtOAc. The organic layer was dried with MgSO4, and purified by column chromatography to give the title compound (0.7 g, 58%).

[0996] <1>H NMR (CDCl<3>) δ 7.05 (2H, m), 6.37 (1H, m), 5.81 (2H, m), 3.68 (3H, s), 1.51 (3H, d)[0996] <1>H NMR (CDCl<3>) δ 7.05 (2H, m), 6.37 (1H, m), 5.81 (2H, m), 3.68 (3H, s), 1.51 (3H, d)

[0998] Primer pripreme 116: metil (4R)-4-(4-bromo-2,6-difluoro-fenoksi)pentanoat[0998] Preparation example 116: methyl (4R)-4-(4-bromo-2,6-difluoro-phenoxy)pentanoate

[0999] Metil (Z,4R)-4-(4-bromo-2,6-difluoro-fenoksi)pent-2-enoat (0.66 g, 2 mmol) dobijen u primeru pripreme 115 je izreagovan na isti način kao u fazi B primera pripreme 50 da bi se dobilo naslovno jedinjenje (0.45 g, 70%).[0999] Methyl (Z,4R)-4-(4-bromo-2,6-difluoro-phenoxy)pent-2-enoate (0.66 g, 2 mmol) obtained in Preparative Example 115 was reacted in the same manner as in Step B of Preparative Example 50 to give the title compound (0.45 g, 70%).

[1000] 1H NMR (CDCl<3>) δ 7.08 (2H, m), 4.28 (1H, m), 3.69 (3H, s), 2.58 (2H, t), 2.00 (2H, m), 1.27 (3H, d)[1000] 1H NMR (CDCl<3>) δ 7.08 (2H, m), 4.28 (1H, m), 3.69 (3H, s), 2.58 (2H, t), 2.00 (2H, m), 1.27 (3H, d)

[1002] Primer pripreme 117: metil (4R)-4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]pentanoat[1002] Preparation example 117: methyl (4R)-4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pentanoate

[1003] Metil (4R)-4-(4-bromo-2,6-difluoro-fenoksi)pentanoat (0.45 g, 1.4 mmol) dobijen u primeru pripreme 116 je izreagovan na isti način kao u fazi A primera pripreme 1 da bi se dobilo naslovno jedinjenje (0.062 g, 13%).[1003] Methyl (4R)-4-(4-bromo-2,6-difluoro-phenoxy)pentanoate (0.45 g, 1.4 mmol) obtained in Preparative Example 116 was reacted in the same manner as in Step A of Preparative Example 1 to give the title compound (0.062 g, 13%).

[1004] 1H NMR (CDCl<3>) δ 7.31 (2H, m), 4.38 (1H, m), 3.68 (3H, s), 2.59 (2H, t), 2.00 (2H, m), 1.32 (12H, s), 1.25 (3H, d)[1004] 1H NMR (CDCl<3>) δ 7.31 (2H, m), 4.38 (1H, m), 3.68 (3H, s), 2.59 (2H, t), 2.00 (2H, m), 1.32 (12H, s), 1.25 (3H, d)

[1006] Primer pripreme 118: metil (2S)-2-(4-bromo-2,6-difluoro-fenoksi) propanoat[1006] Preparation example 118: methyl (2S)-2-(4-bromo-2,6-difluoro-phenoxy) propanoate

[1007] 4-bromo-2,6-difluoro-fenol (1.0 g, 4.7 mmol) dobijen u fazi A primera pripreme 2 i (R)-metil laktat(0.49 g, 4.7 mmol) su izreagovani na isti način kao u fazi C primera pripreme 27 da bi se dobilo naslovno jedinjenje (1.17 g, 83%).[1007] 4-Bromo-2,6-difluoro-phenol (1.0 g, 4.7 mmol) obtained in Step A of Preparative Example 2 and (R)-methyl lactate (0.49 g, 4.7 mmol) were reacted in the same manner as in Step C of Preparative Example 27 to give the title compound (1.17 g, 83%).

[1008] <1>H-NMR (CDCl<3>) δ 7.08 (2H, m), 4.79 (1H, m), 3.77 (3H, s), 1.62 (3H, d)[1008] <1>H-NMR (CDCl<3>) δ 7.08 (2H, m), 4.79 (1H, m), 3.77 (3H, s), 1.62 (3H, d)

[1010] Primer pripreme 119: (2S)-2-(4-bromo-2,6-difluoro-fenoksi)propan-1-ol[1010] Preparation example 119: (2S)-2-(4-bromo-2,6-difluoro-phenoxy)propan-1-ol

[1011] Metil (2S)-2-(4-bromo-2,6-difluoro-fenoksi)propanoat (1.17 g, 4.0 mmol) dobijen u primeru pripreme 118 je izreagovan na isti način kao u fazi A primera pripreme 30 da bi se dobilo naslovno jedinjenje (0.9 g, 85%).[1011] Methyl (2S)-2-(4-bromo-2,6-difluoro-phenoxy)propanoate (1.17 g, 4.0 mmol) obtained in Preparative Example 118 was reacted in the same manner as in Step A of Preparative Example 30 to give the title compound (0.9 g, 85%).

[1012] 1H NMR (CDCl<3>) δ 7.10 (2H, m), 4.33 (1H, m), 3.75 (1H, m), 3.70 (1H, m), 2.08 (1H, brs), 1.31 (3H, d)[1012] 1H NMR (CDCl<3>) δ 7.10 (2H, m), 4.33 (1H, m), 3.75 (1H, m), 3.70 (1H, m), 2.08 (1H, brs), 1.31 (3H, d)

[1014] Primer pripreme 120: (2S)-2-(4-bromo-2,6-difluoro-fenoksi)propanal[1014] Preparation example 120: (2S)-2-(4-bromo-2,6-difluoro-phenoxy)propanal

[1015] (2S)-2-(4-bromo-2,6-difluoro-fenoksi)propan-1-ol (0.9 g, 3.3 mmol) dobijen u primeru pripreme 119 je izreagovan na isti način kao u primeru pripreme 114 da bi se dobilo naslovno jedinjenje (0.61 g, 68%).[1015] (2S)-2-(4-bromo-2,6-difluoro-phenoxy)propan-1-ol (0.9 g, 3.3 mmol) obtained in Preparation Example 119 was reacted in the same manner as in Preparation Example 114 to give the title compound (0.61 g, 68%).

[1016] 1H NMR (CDCl<3>) δ 9.85 (1H, s), 7.13 (2H, m), 4.51 (1H, m), 1.48 (3H, d)[1016] 1H NMR (CDCl<3>) δ 9.85 (1H, s), 7.13 (2H, m), 4.51 (1H, m), 1.48 (3H, d)

[1018] Primer pripreme 121: etil (E,4S)-4-(4-bromo-2,6-difluoro-fenoksi)pent-2-enoat[1018] Preparation example 121: ethyl (E,4S)-4-(4-bromo-2,6-difluoro-phenoxy)pent-2-enoate

[1019] (2S)-2-(4-bromo-2,6-difluoro-fenoksi)propanal (0.61 g, 2.3 mmol) dobijen u primeru pripreme 120 i etil(trifenilfosforaniliden)acetat (0.8 g, 2.3 mmol) su izreagovani na isti način kao u fazi A primera pripreme 50 da bi se dobilo naslovno jedinjenje (0.69 g, 90%, E/Z=2/1).[1019] (2S)-2-(4-Bromo-2,6-difluoro-phenoxy)propanal (0.61 g, 2.3 mmol) obtained in Preparative Example 120 and ethyl (triphenylphosphoranylidene)acetate (0.8 g, 2.3 mmol) were reacted in the same manner as in Step A of Preparative Example 50 to give the title compound (0.69 g, 90% yield). E/Z=2/1).

[1020] 1H NMR (CDCl<3>) δ (Z-izomer) 7.05 (2H, m), 6.34 (1H, m), 5.81 (2H, m), 4.14 (2H, q), 1.51 (3H, d), 1.26 (3H, t)[1020] 1H NMR (CDCl<3>) δ (Z-isomer) 7.05 (2H, m), 6.34 (1H, m), 5.81 (2H, m), 4.14 (2H, q), 1.51 (3H, d), 1.26 (3H, t)

[1021] (E-izomer) δ 7.08 (2H, m), 6.93 (1H, m), 6.03 (1H, d), 4.83 (1H, m), 4.20 (2H, q), 1.48 (3H, d), 1.29 (3H, t)[1021] (E-isomer) δ 7.08 (2H, m), 6.93 (1H, m), 6.03 (1H, d), 4.83 (1H, m), 4.20 (2H, q), 1.48 (3H, d), 1.29 (3H, t)

[1023] Primer pripreme 122: etil (4S)-4-(4-bromo-2,6-difluoro-fenoksi)pentanoat[1023] Preparation example 122: ethyl (4S)-4-(4-bromo-2,6-difluoro-phenoxy)pentanoate

[1024] Etil(E,4S)-4-(4-bromo-2,6-difluoro-fenoksi)pent-2-enoat (0.49 g, 1.4 mmol) dobijen u primeru pripreme 121 je izreagovan na isti način kao u fazi B primera pripreme 50 da bi se dobilo naslovno jedinjenje (0.326 g, 71%).[1024] Ethyl (E,4S)-4-(4-bromo-2,6-difluoro-phenoxy)pent-2-enoate (0.49 g, 1.4 mmol) obtained in Preparative Example 121 was reacted in the same manner as in Step B of Preparative Example 50 to give the title compound (0.326 g, 71%).

[1025] 1H NMR (CDCl<3>) δ 7.08 (2H, m), 4.29 (1H, m), 4.14 (2H, q), 2.58 (2H, t), 2.00 (2H, m), 1.27 (6H, m) Primer pripreme 123: etil (4S)-4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]pentanoat[1025] 1H NMR (CDCl<3>) δ 7.08 (2H, m), 4.29 (1H, m), 4.14 (2H, q), 2.58 (2H, t), 2.00 (2H, m), 1.27 (6H, m) Preparation example 123: ethyl (4S)-4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pentanoate

[1026] Etil (4S)-4-(4-bromo-2,6-difluoro-fenoksi)pentanoat (0.326 g, 1 mmol) dobijen u primeru pripreme 122 je izreagovan na isti način kao u fazi A primera pripreme 1 da bi se dobilo naslovno jedinjenje (0.237 g, 62%).[1026] Ethyl (4S)-4-(4-bromo-2,6-difluoro-phenoxy)pentanoate (0.326 g, 1 mmol) obtained in Preparative Example 122 was reacted in the same manner as in Step A of Preparative Example 1 to give the title compound (0.237 g, 62%).

[1027] 1H NMR (CDCl<3>) δ 7.31 (2H, m), 4.37 (1H, m), 4.13 (2H, q), 2.58 (2H, t), 2.00 (2H, m), 1.33 (12H, s), 1.27 (6H, m)[1027] 1H NMR (CDCl<3>) δ 7.31 (2H, m), 4.37 (1H, m), 4.13 (2H, q), 2.58 (2H, t), 2.00 (2H, m), 1.33 (12H, s), 1.27 (6H, m)

[1029] Primer pripreme 124: 1-(6-hloro-2-piridil)-N,N-dimetil-pirolidin-3-amin[1029] Preparation example 124: 1-(6-chloro-2-pyridyl)-N,N-dimethyl-pyrrolidin-3-amine

[1030] 2,6-dihloropiridin (1 g, 6.75 mmol) i N,N-dimetilpirolidin-3-amin(0.77 g, 6.75 mmol) su izreagovani na isti način kao u primeru pripreme 5 da bi se dobilo naslovno jedinjenje (1.42 g, 90%).[1030] 2,6-Dichloropyridine (1 g, 6.75 mmol) and N,N-dimethylpyrrolidine-3-amine (0.77 g, 6.75 mmol) were reacted in the same manner as in Preparation Example 5 to give the title compound (1.42 g, 90%).

[1031] 1H NMR (CDCl<3>) δ7.35 (1H, t), 6.52 (1H, m), 6.20 (1H, m), 3.75 (1H, m), 3.63 (1H, m), 3.39 (1H, m), 3.22 (1H, m), 2.78 (1H, m), 2.31 (6H, s), 2.23 (1H, m), 1.93 (1H, m)[1031] 1H NMR (CDCl<3>) δ7.35 (1H, t), 6.52 (1H, m), 6.20 (1H, m), 3.75 (1H, m), 3.63 (1H, m), 3.39 (1H, m), 3.22 (1H, m), 2.78 (1H, m), 2.31 (6H, s), 2.23 (1H, m), 1.93 (1H, m)

[1033] Primer pripreme 125: 2-hloro-6-izopropilsulfanil-piridin[1033] Preparation example 125: 2-chloro-6-isopropylsulfanyl-pyridine

[1034] 2,6-dihloropiridin (3.0 g, 20.3 mmol) i propan-2-tiol(1.88 mL, 20.3 mmol) su izreagovani na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (3.63 g, 95 %).[1034] 2,6-Dichloropyridine (3.0 g, 20.3 mmol) and propane-2-thiol (1.88 mL, 20.3 mmol) were reacted in the same manner as in Preparation Example 37 to give the title compound (3.63 g, 95 %).

[1035] <1>H-NMR (CDCl<3>) δ 7.40(1H, t), 7.05(1H, t), 6.98(1H, t), 4.00(1H, m), 1.40(6H, d)[1035] <1>H-NMR (CDCl<3>) δ 7.40(1H, t), 7.05(1H, t), 6.98(1H, t), 4.00(1H, m), 1.40(6H, d)

[1037] Primer pripreme 126: 2-hloro-6-fenoksi-piridin[1037] Preparation example 126: 2-chloro-6-phenoxy-pyridine

[1038] 2,6-dihloropiridin (2.0 g, 13.5 mmol) i fenol (1.4 mL, 14.9 mmol) su izreagovani na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (3.5 g, 84 %).[1038] 2,6-Dichloropyridine (2.0 g, 13.5 mmol) and phenol (1.4 mL, 14.9 mmol) were reacted in the same manner as in Preparation Example 37 to give the title compound (3.5 g, 84 %).

[1039] <1>H-NMR (CDCl<3>) δ 7.62(1H, t), 7.41(2H, m), 7.21(1H, t), 7.14(2H, d), 6.74(2H, d)[1039] <1>H-NMR (CDCl<3>) δ 7.62(1H, t), 7.41(2H, m), 7.21(1H, t), 7.14(2H, d), 6.74(2H, d)

[1041] Primer pripreme 127: 2-bromo-5-metoksi-fenol[1041] Preparation example 127: 2-bromo-5-methoxy-phenol

[1042] Nakon što je 3-metoksi-fenol (1 g, 8.05 mmol) rastvoren u CS<2>(4 mL), dodat je Br<2>(0.4 mL), i mešavina je mešana na sobnoj temperaturi 2 sata. Reaktant je dodat sa Na<2>S<2>O<3>vodenim rastvorom a zatim je ekstrahovan sa EtOAc. Organski sloj je izdvojen i osušen sa MgSO<4>, i koncentrovan je pod smanjenim pritiskom da bi se dobilo naslovno jedinjenje (1.05 g, 64 %).[1042] After 3-methoxy-phenol (1 g, 8.05 mmol) was dissolved in CS<2> (4 mL), Br<2> (0.4 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reactant was added with Na<2>S<2>O<3> aqueous solution and then extracted with EtOAc. The organic layer was separated and dried with MgSO<4> , and concentrated under reduced pressure to give the title compound (1.05 g, 64 %).

[1043] <1>H-NMR (CDCl<3>) δ 7.31 (1H, d), 6.59 (1H, m), 6.40 (1H, m), 5.45 (1H, s), 3.79 (3H, s).[1043] <1>H-NMR (CDCl<3>) δ 7.31 (1H, d), 6.59 (1H, m), 6.40 (1H, m), 5.45 (1H, s), 3.79 (3H, s).

[1045] Primer pripreme 128: 1-bromo-2-ciklopentiloksi-4-metoksi-benzen[1045] Preparation example 128: 1-bromo-2-cyclopentyloxy-4-methoxy-benzene

[1046] 2-bromo-5-metoksi-fenol (0.2 g, 0.98 mmol) dobijen u primeru pripreme 127, bromo-ciklopentan (0.16 mL) i Cs<2>CO<3>(0.96 g) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.26 g, 96 %).[1046] 2-Bromo-5-methoxy-phenol (0.2 g, 0.98 mmol) obtained in Preparative Example 127, bromo-cyclopentane (0.16 mL) and Cs<2>CO<3> (0.96 g) were reacted in the same manner as in Step B of Preparative Example 44 to give the title compound (0.26 g, 96%).

[1047] <1>H-NMR (CDCl<3>) δ 7.38 (1H, d), 6.47 (1H, m), 6.36 (1H, m), 4.75 (1H, m), 3.79 (3H, s), 1.88 (6H, m), 1.61 (2H, m).[1047] <1>H-NMR (CDCl<3>) δ 7.38 (1H, d), 6.47 (1H, m), 6.36 (1H, m), 4.75 (1H, m), 3.79 (3H, s), 1.88 (6H, m), 1.61 (2H, m).

[1049] Primer pripreme 129: 2-bromo-1-ciklopentiloksi-f-fluoro-benzen[1049] Preparation Example 129: 2-bromo-1-cyclopentyloxy-f-fluoro-benzene

[1050] 2-bromo-f-fluoro-fenol (0.3 g, 1.57 mmol), bromo-ciklopentan (0.25 mL) i Cs<2>CO<3>(1.53 g) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.38 g, 93%).[1050] 2-Bromo-f-fluoro-phenol (0.3 g, 1.57 mmol), bromo-cyclopentane (0.25 mL) and Cs<2>CO<3> (1.53 g) were reacted in the same manner as in Step B of Preparation Example 44 to give the title compound (0.38 g, 93%).

[1051] <1>H-NMR (CDCl<3>) δ 7.27 (1H, m), 6.94 (1H, m), 6.82 (1H, m), 4.73 (1H, m), 1.86 (6H, m), 1.62 (2H, m).[1051] <1>H-NMR (CDCl<3>) δ 7.27 (1H, m), 6.94 (1H, m), 6.82 (1H, m), 4.73 (1H, m), 1.86 (6H, m), 1.62 (2H, m).

[1053] Primer pripreme 130: 3-bromo-5-metil-piridin-2-ol[1053] Preparation example 130: 3-bromo-5-methyl-pyridin-2-ol

[1054] 5-metil-piridin-2-ol (1 g, 9.16 mmol) i Br<2>(0.47 mL) su izreagovani na isti način kao u primeru pripreme 127 da bi se dobilo naslovno jedinjenje (1.7 g, 98%).[1054] 5-Methyl-pyridin-2-ol (1 g, 9.16 mmol) and Br<2> (0.47 mL) were reacted in the same manner as in Preparation Example 127 to give the title compound (1.7 g, 98%).

[1055] <1>H-NMR (CDCl<3>) δ 7.73 (1H, s), 7.22 (1H, s), 2.10 (3H, s).[1055] <1>H-NMR (CDCl<3>) δ 7.73 (1H, s), 7.22 (1H, s), 2.10 (3H, s).

[1057] Primer pripreme 131: 3-bromo-2-ciklopentiloksi-5-metil-piridin[1057] Preparation example 131: 3-bromo-2-cyclopentyloxy-5-methyl-pyridine

[1058] 3-bromo-5-metil-piridin-2-ol (0.5 g, 2.66 mmol) dobijen u primeru pripreme 130, bromociklopentan (0.43 mL) i Cs<2>CO<3>(2.6 g) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.25 g, 37%).[1058] 3-Bromo-5-methyl-pyridin-2-ol (0.5 g, 2.66 mmol) obtained in Preparative Example 130, bromocyclopentane (0.43 mL) and Cs<2>CO<3> (2.6 g) were reacted in the same manner as in Step B of Preparative Example 44 to give the title compound (0.25 g, 37%).

[1059] <1>H-NMR (CDCl<3>) δ 7.86 (1H, s), 7.60 (1H, s), 5.38 (1H, m), 2.21 (3H, s), 1.93 (2H, m), 1.82 (4H, m), 1.61 (2H, m).[1059] <1>H-NMR (CDCl<3>) δ 7.86 (1H, s), 7.60 (1H, s), 5.38 (1H, m), 2.21 (3H, s), 1.93 (2H, m), 1.82 (4H, m), 1.61 (2H, m).

[1061] Primer pripreme 132: 1-bromo-2-izopropoksi-4-metoksi-benzen[1061] Preparation example 132: 1-bromo-2-isopropoxy-4-methoxy-benzene

[1062] 2-bromo-5-metoksi-fenol (0.2 g, 0.98 mmol) dobijen u primeru pripreme 127, 2-bromo-propan (0.14 mL) i Cs<2>CO<3>(0.96 g) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.23 g, 94%).[1062] 2-Bromo-5-methoxy-phenol (0.2 g, 0.98 mmol) obtained in Preparative Example 127, 2-bromo-propane (0.14 mL) and Cs<2>CO<3> (0.96 g) were reacted in the same manner as in Step B of Preparative Example 44 to give the title compound (0.23 g, 94%).

[1063] <1>H-NMR (CDCl<3>) δ 7.39 (1H, d), 6.48 (1H, m), 6.39 (1H, m), 4.51 (1H, m), 3.77 (3H, s), 1.37 (6H, d).[1063] <1>H-NMR (CDCl<3>) δ 7.39 (1H, d), 6.48 (1H, m), 6.39 (1H, m), 4.51 (1H, m), 3.77 (3H, s), 1.37 (6H, d).

[1065] Primer pripreme 133: 3-bromo-2-izopropoksi-5-metil-piridin[1065] Preparation example 133: 3-bromo-2-isopropoxy-5-methyl-pyridine

[1066] 3-bromo-5-metil-piridin-2-ol (0.3 g, 2.66 mmol) dobijen u primeru pripreme 130, 2-bromopropan (0.22 mL) i Cs<2>CO<3>(1.56 g) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.09 g, 25%).[1066] 3-Bromo-5-methyl-pyridin-2-ol (0.3 g, 2.66 mmol) obtained in Preparative Example 130, 2-bromopropane (0.22 mL) and Cs<2>CO<3> (1.56 g) were reacted in the same manner as in Step B of Preparative Example 44 to give the title compound (0.09 g, 25%).

[1067] <1>H-NMR (CDCl<3>) δ 7.85 (1H, s), 7.62 (1H, s), 5.26 (1H, m), 2.21 (3H, s), 1.35 (6H, d).[1067] <1>H-NMR (CDCl<3>) δ 7.85 (1H, s), 7.62 (1H, s), 5.26 (1H, m), 2.21 (3H, s), 1.35 (6H, d).

[1069] Primer pripreme 134: 2-bromo-f-fluoro-1-izopropoksi-benzen[1069] Preparation Example 134: 2-bromo-f-fluoro-1-isopropoxy-benzene

[1070] 2-bromo-f-fluoro-fenol (0.3 g, 1.57 mmol), 2-bromo-propan (0.22 mL) i Cs<2>CO<3>(1.53 g) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.33 g, 89%).[1070] 2-bromo-f-fluoro-phenol (0.3 g, 1.57 mmol), 2-bromo-propane (0.22 mL) and Cs<2>CO<3> (1.53 g) were reacted in the same manner as in Step B of Preparation Example 44 to give the title compound (0.33 g, 89%).

[1071] <1>H-NMR (CDCl<3>) δ 7.28 (1H, m), 6.94 (1H, m), 6.88 (1H, m), 4.44 (1H, m), 1.32 (6H, d).[1071] <1>H-NMR (CDCl<3>) δ 7.28 (1H, m), 6.94 (1H, m), 6.88 (1H, m), 4.44 (1H, m), 1.32 (6H, d).

[1073] Primer pripreme 135: 3-bromo-6-metil-piridin-2-ol[1073] Preparation example 135: 3-bromo-6-methyl-pyridin-2-ol

[1074] 6-metil-piridin-2-ol (0.3 g, 2.7 mmol) i Br<2>(0.14 mL) su izreagovani na isti način kao u primeru pripreme 127 da bi se dobilo naslovno jedinjenje (0.09 g, 18%).[1074] 6-Methyl-pyridin-2-ol (0.3 g, 2.7 mmol) and Br<2> (0.14 mL) were reacted in the same manner as in Preparation Example 127 to give the title compound (0.09 g, 18%).

[1075] <1>H-NMR (CDCl<3>) δ 7.48 (1H, d), 6.32 (1H, d), 2.43 (3H, s).[1075] <1>H-NMR (CDCl<3>) δ 7.48 (1H, d), 6.32 (1H, d), 2.43 (3H, s).

[1077] Primer pripreme 136: 3-bromo-2-ciklopentiloksi-6-metil-piridin[1077] Preparation example 136: 3-bromo-2-cyclopentyloxy-6-methyl-pyridine

[1078] 3-bromo-6-metil-piridin-2-ol (0.09 g, 0.50 mmol) dobijen u primeru pripreme 135, bromociklopentan (0.08 mL) i Cs<2>CO<3>(0.49 g) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.12 g, 93%).[1078] 3-Bromo-6-methyl-pyridin-2-ol (0.09 g, 0.50 mmol) obtained in Preparative Example 135, bromocyclopentane (0.08 mL) and Cs<2>CO<3> (0.49 g) were reacted in the same manner as in Step B of Preparative Example 44 to give the title compound (0.12 g, 93%).

[1079] <1>H-NMR (CDCl<3>) δ 7.60 (1H, d), 6.40 (1H, d), 5.30 (1H, m), 2.53 (3H, s), 1.94 (2H, m), 1.78 (4H, m), 1.61 (2H, m).[1079] <1>H-NMR (CDCl<3>) δ 7.60 (1H, d), 6.40 (1H, d), 5.30 (1H, m), 2.53 (3H, s), 1.94 (2H, m), 1.78 (4H, m), 1.61 (2H, m).

[1081] Primer pripreme 137: 2-bromo-6-fluoro-4-metil-fenol[1081] Preparation example 137: 2-bromo-6-fluoro-4-methyl-phenol

[1082] 2-fluoro-4-metil-fenol (0.4 g, 3.17 mmol) i Br<2>(0.16 mL) su izreagovani na isti način kao u primeru pripreme 127 da bi se dobilo naslovno jedinjenje (0.37 g, 56%).[1082] 2-Fluoro-4-methyl-phenol (0.4 g, 3.17 mmol) and Br<2> (0.16 mL) were reacted in the same manner as in Preparation Example 127 to give the title compound (0.37 g, 56%).

[1083] <1>H-NMR (CDCl<3>) δ 7.07 (1H, s), 6.87 (1H, m), 5.32 (1H, s), 2.26 (3H, s).[1083] <1>H-NMR (CDCl<3>) δ 7.07 (1H, s), 6.87 (1H, m), 5.32 (1H, s), 2.26 (3H, s).

[1085] Primer pripreme 138: 1-bromo-3-fluoro-2-izopropoksi-5-metil-benzen[1085] Preparation example 138: 1-bromo-3-fluoro-2-isopropoxy-5-methyl-benzene

[1086] 2-bromo-6-fluoro-4-metil-fenol (0.10 g, 0.49 mmol) dobijen u primeru pripreme 137, 2-bromopropan (0.07 mL) i Cs<2>CO<3>(0.48 g) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.11 g, 88%).[1086] 2-Bromo-6-fluoro-4-methyl-phenol (0.10 g, 0.49 mmol) obtained in Preparative Example 137, 2-bromopropane (0.07 mL) and Cs<2>CO<3> (0.48 g) were reacted in the same manner as in Step B of Preparative Example 44 to give the title compound (0.11 g, 88%).

[1087] <1>H-NMR (CDCl<3>) δ 7.12 (1H, s), 6.84 (1H, m), 4.45 (1H, m), 2.26 (3H, s), 1.34 (6H, d).[1087] <1>H-NMR (CDCl<3>) δ 7.12 (1H, s), 6.84 (1H, m), 4.45 (1H, m), 2.26 (3H, s), 1.34 (6H, d).

[1089] Primer pripreme 139: 1-bromo-3-fluoro-5-metil-2-propoksi-benzen[1089] Preparation Example 139: 1-bromo-3-fluoro-5-methyl-2-propoxy-benzene

[1090] 2-bromo-6-fluoro-4-metil-fenol (0.10 g, 0.49 mmol) dobijen u primeru pripreme 137, 1-bromopropan (0.07 mL) i Cs<2>CO<3>(0.48 g) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.10 g, 85%).[1090] 2-Bromo-6-fluoro-4-methyl-phenol (0.10 g, 0.49 mmol) obtained in Preparative Example 137, 1-bromopropane (0.07 mL) and Cs<2>CO<3> (0.48 g) were reacted in the same manner as in Step B of Preparative Example 44 to give the title compound (0.10 g, 85%).

[1091] <1>H-NMR (CDCl<3>) δ 7.11 (1H, s), 6.83 (1H, m), 3.99 (2H, t), 2.26 (3H, s), 1.80 (2H, m), 1.05 (3H, t).[1091] <1>H-NMR (CDCl<3>) δ 7.11 (1H, s), 6.83 (1H, m), 3.99 (2H, t), 2.26 (3H, s), 1.80 (2H, m), 1.05 (3H, t).

[1093] Primer pripreme 140: 1-bromo-2,4-dipropoksi-benzen[1093] Preparation example 140: 1-bromo-2,4-dipropoxy-benzene

[1094] 4-bromo-benzen-1,3-diol (0.1 g, 0.53 mmol), 1-bromo-propan (0.10 mL) i Cs<2>CO<3>(0.52 g) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.13 g, 93%).[1094] 4-Bromo-benzene-1,3-diol (0.1 g, 0.53 mmol), 1-bromo-propane (0.10 mL) and Cs<2>CO<3> (0.52 g) were reacted in the same manner as in Step B of Preparation Example 44 to give the title compound (0.13 g, 93%).

[1095] <1>H-NMR (CDCl<3>) δ 7.37 (1H, d), 6.46 (1H, m), 6.36 (1H, m), 3.94 (2H, t), 3.86 (2H, t), 1.84 (2H, m), 1.78 (2H, m), 1.06 (3H, t), 1.02 (3H, t).[1095] <1>H-NMR (CDCl<3>) δ 7.37 (1H, d), 6.46 (1H, m), 6.36 (1H, m), 3.94 (2H, t), 3.86 (2H, t), 1.84 (2H, m), 1.78 (2H, m), 1.06 (3H, t), 1.02 (3H, t).

[1097] Primer pripreme 141: 2-bromo-3-fluoro-4-metil-fenol[1097] Preparation example 141: 2-bromo-3-fluoro-4-methyl-phenol

[1098] 3-fluoro-4-metil-fenol (0.3 g, 2.38 mmol) i Br<2>(0.12 mL) su izreagovani na isti način kao u primeru pripreme 127 da bi se dobilo naslovno jedinjenje (0.37 g, 75%).[1098] 3-Fluoro-4-methyl-phenol (0.3 g, 2.38 mmol) and Br<2> (0.12 mL) were reacted in the same manner as in Preparation Example 127 to give the title compound (0.37 g, 75%).

[1099] <1>H-NMR (CDCl<3>) δ 7.03 (1H, m), 6.83 (1H, m), 5.35 (1H, s), 2.26 (3H, s).[1099] <1>H-NMR (CDCl<3>) δ 7.03 (1H, m), 6.83 (1H, m), 5.35 (1H, s), 2.26 (3H, s).

[1101] Primer pripreme 142: 2-bromo-1-ciklopentiloksi-3-fluoro-4-metil-benzen[1101] Preparation example 142: 2-bromo-1-cyclopentyloxy-3-fluoro-4-methyl-benzene

[1102] 2-bromo-3-fluoro-4-metil-fenol (0.10 g, 0.49 mmol) dobijen u primeru pripreme 141, bromociklopentan (0.08 mL) i Cs<2>CO<3>(0.48 g) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.09 g, 67%).[1102] 2-Bromo-3-fluoro-4-methyl-phenol (0.10 g, 0.49 mmol) obtained in Preparative Example 141, bromocyclopentane (0.08 mL) and Cs<2>CO<3> (0.48 g) were reacted in the same manner as in Step B of Preparative Example 44 to give the title compound (0.09 g, 67%).

[1103] <1>H-NMR (CDCl<3>) δ 7.11 (1H, m), 6.84 (1H, m), 4.66 (1H, m), 2.29 (3H, s), 1.90 (4H, m), 1.75 (2H, m), 1.60 (2H, m).[1103] <1>H-NMR (CDCl<3>) δ 7.11 (1H, m), 6.84 (1H, m), 4.66 (1H, m), 2.29 (3H, s), 1.90 (4H, m), 1.75 (2H, m), 1.60 (2H, m).

[1105] Primer pripreme 143: 2-bromo-6-fluoro-fenol[1105] Preparation example 143: 2-bromo-6-fluoro-phenol

[1106] 2-fluoro-fenol (0.32 g, 2.85 mmol) i Br<2>(0.14 mL) su izreagovani na isti način kao u primeru pripreme 127 da bi se dobilo naslovno jedinjenje (0.53 g, 97%).[1106] 2-Fluoro-phenol (0.32 g, 2.85 mmol) and Br<2> (0.14 mL) were reacted in the same manner as in Preparation Example 127 to give the title compound (0.53 g, 97%).

[1107] <1>H-NMR (CDCl<3>) δ 7.25 (1H, m), 7.14 (1H, d), 6.88 (1H, t), 5.20 (1H, s).[1107] <1>H-NMR (CDCl<3>) δ 7.25 (1H, m), 7.14 (1H, d), 6.88 (1H, t), 5.20 (1H, s).

[1109] Primer pripreme 144: 1-bromo-2-ciklopentiloksi-3-fluoro-benzen[1109] Preparation example 144: 1-bromo-2-cyclopentyloxy-3-fluoro-benzene

[1110] 2-bromo-6-fluoro-fenol (0.10 g, 0.52 mmol) dobijen u primeru pripreme 143, bromo-ciklopentan (0.08 mL) i Cs<2>CO<3>(0.51 g) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.13 g, 96%).[1110] 2-Bromo-6-fluoro-phenol (0.10 g, 0.52 mmol) obtained in Preparative Example 143, bromo-cyclopentane (0.08 mL) and Cs<2>CO<3> (0.51 g) were reacted in the same manner as in Step B of Preparative Example 44 to give the title compound (0.13 g, 96%).

[1111] <1>H-NMR (CDCl<3>) δ 7.23 (1H, m), 7.15 (1H, m), 6.83 (1H, t), 4.75 (1H, m), 1.89-1.78 (6H, m), 1.63 (2H, m).[1111] <1>H-NMR (CDCl<3>) δ 7.23 (1H, m), 7.15 (1H, m), 6.83 (1H, t), 4.75 (1H, m), 1.89-1.78 (6H, m), 1.63 (2H, m).

[1113] Primer pripreme 145: 1-bromo-2-ciklopentiloksi-3-fluoro-5-metil-benzen[1113] Preparation example 145: 1-bromo-2-cyclopentyloxy-3-fluoro-5-methyl-benzene

[1114] 2-bromo-6-fluoro-4-metil-fenol (0.10 g, 0.49 mmol) dobijen u primeru pripreme 137, bromociklopentan (0.08 mL) i Cs<2>CO<3>(0.48 g) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.12 g, 87%).[1114] 2-Bromo-6-fluoro-4-methyl-phenol (0.10 g, 0.49 mmol) obtained in Preparative Example 137, bromocyclopentane (0.08 mL) and Cs<2>CO<3> (0.48 g) were reacted in the same manner as in Step B of Preparative Example 44 to give the title compound (0.12 g, 87%).

[1115] <1>H-NMR (CDCl<3>) δ 7.13 (1H, s), 6.84 (1H, d), 4.87 (1H, m), 2.27 (3H, s), 1.94 (4H, m), 1.75 (2H, m), 1.60 (2H, m).[1115] <1>H-NMR (CDCl<3>) δ 7.13 (1H, s), 6.84 (1H, d), 4.87 (1H, m), 2.27 (3H, s), 1.94 (4H, m), 1.75 (2H, m), 1.60 (2H, m).

[1116] Primer pripreme 146: etil 6-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]heksanoat[1116] Preparation Example 146: Ethyl 6-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]hexanoate

[1117] 2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenol (1.11 g, 4.34 mmol) dobijen u fazi B primera pripreme 2, etil 6-bromoheksanoat (0.97 g, 4.34 mmol), i Cs<2>CO<3>(2.83 g, 8.68 mmol) su dodati sa CH<3>CN (15 mL), i mešavina je mešana pod refluksom 2 sata. Ostatak je izdvojen i koncentrovan pod smanjenim pritiskom da bi se dobilo naslovno jedinjenje (1.4 g, 80 %).[1117] 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.11 g, 4.34 mmol) obtained in phase B of Preparation Example 2, ethyl 6-bromohexanoate (0.97 g, 4.34 mmol), and Cs<2>CO<3> (2.83 g, 8.68 mmol) were added with CH<3>CN (15 mL), and the mixture was stirred under reflux for 2 h. The residue was separated and concentrated under reduced pressure to give the title compound (1.4 g, 80 %).

[1118] <1>H-NMR (CDCl<3>) δ 7.31 (2H, m), 4.17 (2H, m), 4.14 (2H, q), 2.32 (2H, t), 1.77 (2H, m), 1.68 (2H, m), 1.51 (2H, m), 1.32 (12H, s), 1.24 (3H, t)[1118] <1>H-NMR (CDCl<3>) δ 7.31 (2H, m), 4.17 (2H, m), 4.14 (2H, q), 2.32 (2H, t), 1.77 (2H, m), 1.68 (2H, m), 1.51 (2H, m), 1.32 (12H, s), 1.24 (3H, t)

[1120] Primer pripreme 147: etil estar 5-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenoksi]-valerijanske kiseline[1120] Preparation Example 147: 5-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-valeric acid ethyl ester

[1121] 2-fluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenol (0.50 g, 2.10 mmol) dobijen u fazi A primera pripreme 4, etil 5-bromopentanoat (0.53 g, 2.52 mmol) i Cs<2>CO<3>(1.37 g, 4.20 mmol) dodati sa CH<3>CN (7 mL), i mešavina je mešana pod refluksom 2 sata. Ostatak je izdvojen i koncentrovan pod smanjenim pritiskom da bi se dobilo naslovno jedinjenje (0.40 g, 52 %).[1121] 2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.50 g, 2.10 mmol) obtained in phase A of Preparation Example 4, ethyl 5-bromopentanoate (0.53 g, 2.52 mmol) and Cs<2>CO<3> (1.37 g, 4.20 mmol) were added with CH<3>CN. (7 mL), and the mixture was stirred under reflux for 2 hours. The residue was separated and concentrated under reduced pressure to give the title compound (0.40 g, 52 %).

[1122] <1>H-NMR (CDCl<3>) δ 7.50 (2H, t), 6.92 (1H, t), 4.13 (2H, q), 4.06 (2H, t), 2.39 (2H, t), 1.92-1.77 (4H, m), 1.32 (12H, s), 1.24(3H, t)[1122] <1>H-NMR (CDCl<3>) δ 7.50 (2H, t), 6.92 (1H, t), 4.13 (2H, q), 4.06 (2H, t), 2.39 (2H, t), 1.92-1.77 (4H, m), 1.32 (12H, s), 1.24(3H, t)

[1124] Primer pripreme 148: etil estar 4-(4-bromo-fenilsulfanil)-buterne kiseline[1124] Preparation example 148: 4-(4-bromo-phenylsulfanyl)-butyric acid ethyl ester

[1125] 4-bromo-benzentiol (0.5 g, 2.64 mmol), NaH (60% u mineralnom ulju, 0.11 g, 2.64 mmol) i etil estar 4-bromo-buterne kiseline (0.42 mL, 2.91 mmol) su izreagovani na isti način kao u primeru pripreme 12 da bi se dobilo naslovno jedinjenje (0.80 g, 99 %).[1125] 4-Bromo-benzenethiol (0.5 g, 2.64 mmol), NaH (60% in mineral oil, 0.11 g, 2.64 mmol) and 4-bromo-butyric acid ethyl ester (0.42 mL, 2.91 mmol) were reacted in the same manner as in Preparative Example 12 to give the title compound (0.80 g, 99%).

[1126] <1>H-NMR (CDCl<3>) δ 7.38 (2H, d), 7.19 (2H, d), 4.13 (2H, q), 2.93 (2H, t), 2.43 (2H, t), 1.93 (2H, m), 1.24 (3H, t).[1126] <1>H-NMR (CDCl<3>) δ 7.38 (2H, d), 7.19 (2H, d), 4.13 (2H, q), 2.93 (2H, t), 2.43 (2H, t), 1.93 (2H, m), 1.24 (3H, t).

[1128] Primer pripreme 149: etil estar 4-(3'-hidroksi-bifenil-4-ilsulfanil)-buterne kiseline[1128] Preparation example 149: 4-(3'-hydroxy-biphenyl-4-ylsulfanyl)-butyric acid ethyl ester

[1129] Etil estar 4-(4-bromo-fenilsulfanil)-buterne kiseline (0.92 g, 3.04 mmol) dobijen u primeru pripreme 148, 3-hidroksifenilborna kiselina (0.42 g, 3.04 mmol), rastvor 2M Na<2>CO<3>(3 mL) i Pd(PPh<3>)<4>(0.18 g, 0.15 mmol) su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.27 g, 28%).[1129] 4-(4-Bromo-phenylsulfanyl)-butyric acid ethyl ester (0.92 g, 3.04 mmol) obtained in preparation example 148, 3-hydroxyphenylboronic acid (0.42 g, 3.04 mmol), a solution of 2M Na<2>CO<3> (3 mL) and Pd(PPh<3>)<4> (0.18 g, 0.15 mmol) were reacted in the same manner as in Preparation Example 13 to give the title compound (0.27 g, 28%).

[1130] <1>H-NMR (CDCl<3>) δ 7.48 (2H, d), 7.38 (2H, d), 7.28 (1H, t), 7.13 (1H, m), 7.02 (1H, m), 6.81 (1H, m), 5.00 (1H, s), 4.13 (2H, q), 2.99 (2H, t), 2.49 (2H, t), 2.00 (2H, m), 1.25 (3H, t).[1130] <1>H-NMR (CDCl<3>) δ 7.48 (2H, d), 7.38 (2H, d), 7.28 (1H, t), 7.13 (1H, m), 7.02 (1H, m), 6.81 (1H, m), 5.00 (1H, s), 4.13 (2H, q), 2.99 (2H, t), 2.49 (2H, t), 2.00 (2H, m), 1.25 (3H, t).

[1132] Primer pripreme 150: metil estar [1-(1-metoksikarbonilmetil-ciklopropilmetildisulfanilmetil)-ciklopropil]-sirćetne kiseline[1132] Preparation Example 150: [1-(1-Methoxycarbonylmethyl-cyclopropylmethyldisulfanylmethyl)-cyclopropyl]-acetic acid methyl ester

[1133] Nakon što je metil estar (1-merkaptometil-ciklopropil)-sirćetne kiseline (1 g, 6.2 mmol) rastvoren u metanolu (20 mL), dodat je I2 (0.79 g, 3.1 mmol), i mešavina je mešana na sobnoj temperaturi 1 sat. Reaktantu je dodata voda a zatim je ekstrahovan sa EtOAc. Organski sloj je izdvojen i osušen sa MgSO<4>, i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.80 g, 40 %).[1133] After (1-mercaptomethyl-cyclopropyl)-acetic acid methyl ester (1 g, 6.2 mmol) was dissolved in methanol (20 mL), I2 (0.79 g, 3.1 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reactant and then extracted with EtOAc. The organic layer was separated and dried with MgSO<4> , and purified by column chromatography to give the title compound (0.80 g, 40 %).

[1134] <1>H-NMR (CDCl<3>) δ 3.68 (6H, s), 2.89 (4H, s), 2.44 (4H, s), 0.62 (4H, m), 0.56 (4H, m).[1134] <1>H-NMR (CDCl<3>) δ 3.68 (6H, s), 2.89 (4H, s), 2.44 (4H, s), 0.62 (4H, m), 0.56 (4H, m).

[1136] Primer pripreme 151: metil estar [1-(4-bromo-2,6-difluoro-fenilsulfanil metil)-ciklopropil]-sirćetne kiseline[1136] Preparation Example 151: [1-(4-bromo-2,6-difluoro-phenylsulfanyl methyl)-cyclopropyl]-acetic acid methyl ester

[1137] Metil estru [1-(1-metoksikarbonilmetil-ciklopropilmetildisulfanilmetil)-ciklopropil]-sirćetne kiseline (0.40 g, 1.25 mmol) dobijenom u primeru pripreme 150 i 4-bromo-2,6-difluoro-fenilaminu (0.2 g, 0.96 mmol) je dodavan N<2>gas na 75°C. Izopentil nitrit (0.33 mL, 2.50 mmol) je polako dodat u kapima, i mešavina je mešana na 75°C 1 sat. Reaktant je koncentrovan pod smanjenim pritiskom i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.10 g, 29%).[1137] To [1-(1-methoxycarbonylmethyl-cyclopropylmethyldisulfanylmethyl)-cyclopropyl]-acetic acid methyl ester (0.40 g, 1.25 mmol) obtained in Preparation Example 150 and 4-bromo-2,6-difluoro-phenylamine (0.2 g, 0.96 mmol) was added N<2>gas at 75°C. Isopentyl nitrite (0.33 mL, 2.50 mmol) was slowly added dropwise, and the mixture was stirred at 75°C for 1 hour. The reactant was concentrated under reduced pressure and purified by column chromatography to give the title compound (0.10 g, 29%).

[1138] <1>H-NMR (CDCl<3>) δ 7.10 (2H, d), 3.66 (3H, s), 2.99 (2H, s), 2.55 (2H, s), 0.45 (2H, m), 0.36 (2H, m).[1138] <1>H-NMR (CDCl<3>) δ 7.10 (2H, d), 3.66 (3H, s), 2.99 (2H, s), 2.55 (2H, s), 0.45 (2H, m), 0.36 (2H, m).

[1140] Primer pripreme 152: metil estar [1-(3,5-difluoro-3'-hidroksi-bifenil-4-ilsulfanilmetil)-ciklopropil]-sirćetne kiseline[1140] Preparation Example 152: [1-(3,5-difluoro-3'-hydroxy-biphenyl-4-ylsulfanylmethyl)-cyclopropyl]-acetic acid methyl ester

[1141] Metil estar [1-(4-bromo-2,6-difluoro-fenilsulfanilmetil)-ciklopropil]-sirćetne kiseline (0.10 g, 0.28 mmol) dobijen u primeru pripreme 151, 3-hidroksifenilborna kiselina (0.04 g, 0.28 mmol), 2M Na<2>CO<3>vodeni rastvor (0.3 mL) i Pd(PPh<3>)<4>(0.02 g, 0.01 mmol) su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.02 g, 19%).[1141] [1-(4-Bromo-2,6-difluoro-phenylsulfanylmethyl)-cyclopropyl]-acetic acid methyl ester (0.10 g, 0.28 mmol) obtained in Preparation Example 151, 3-hydroxyphenylboronic acid (0.04 g, 0.28 mmol), 2M Na<2>CO<3> and aqueous solution (0.3 mL) Pd(PPh<3>)<4> (0.02 g, 0.01 mmol) were reacted in the same manner as in Preparation Example 13 to give the title compound (0.02 g, 19%).

[1142] <1>H-NMR (CDCl<3>) δ 7.32 (1H, t), 7.12 (3H, m), 7.03 (1H, s), 6.89 (1H, m), 5.51 (1H, s), 3.65 (3H, s), 3.00 (2H, s), 2.57 (2H, s), 0.45-0.39 (4H, m).[1142] <1>H-NMR (CDCl<3>) δ 7.32 (1H, t), 7.12 (3H, m), 7.03 (1H, s), 6.89 (1H, m), 5.51 (1H, s), 3.65 (3H, s), 3.00 (2H, s), 2.57 (2H, s), 0.45-0.39 (4H, m).

[1144] Primer pripreme 153: metil estar metoksikarbonilmetildisulfanil-sirćetne kiseline[1144] Preparation Example 153: Methoxycarbonylmethyldisulfanyl-acetic acid methyl ester

[1145] Metil estar merkapto-sirćetne kiseline (1 g, 9.4 mmol) i I<2>(1.19 g, 4.7 mmol) su izreagovani na isti način kao u primeru pripreme 150 da bi se dobilo naslovno jedinjenje (0.50 g, 25 %).[1145] Mercapto-acetic acid methyl ester (1 g, 9.4 mmol) and I<2> (1.19 g, 4.7 mmol) were reacted in the same manner as in Preparation Example 150 to give the title compound (0.50 g, 25 %).

[1146] <1>H-NMR (CDCl<3>) δ 3.75 (6H, s), 3.58 (4H, s).[1146] <1>H-NMR (CDCl<3>) δ 3.75 (6H, s), 3.58 (4H, s).

[1148] Primer pripreme 154: metil estar (4-bromo-2,6-difluoro-fenilsulfanil)-sirćetne kiseline[1148] Preparation Example 154: (4-bromo-2,6-difluoro-phenylsulfanyl)-acetic acid methyl ester

[1149] Metil estar metoksikarbonilmetildisulfanil-sirćetne kiseline (0.9 g, 4.28 mmol) dobijen u primeru pripreme 153, 4-bromo-2,6-difluoro-fenilamin (0.5 g, 2.40 mmol) i izopentilnitrit (0.84 mL, 6.25 mmol) su izreagovani na isti način kao u primeru pripreme 151 da bi se dobilo naslovno jedinjenje (0.30 g, 42 %).[1149] Methoxycarbonylmethyldisulfanylacetic acid methyl ester (0.9 g, 4.28 mmol) obtained in Preparation Example 153, 4-bromo-2,6-difluoro-phenylamine (0.5 g, 2.40 mmol) and isopentyl nitrite (0.84 mL, 6.25 mmol) were reacted in the same manner as in Preparation Example 151 to give the title compound. (0.30 g, 42 %).

[1150] <1>H-NMR (CDCl<3>) δ 7.13 (2H, d), 3.67 (3H, s), 3.52 (2H, s).[1150] <1>H-NMR (CDCl<3>) δ 7.13 (2H, d), 3.67 (3H, s), 3.52 (2H, s).

[1151] Primer pripreme 155: metil estar (3,5-difluoro-3'-hidroksi-bifenil-4-ilsulfanil)-sirćetne kiseline [0438] Metil estar (4-bromo-2,6-difluoro-fenilsulfanil)-sirćetne kiseline (0.12 g, 0.40 mmol) dobijen u primeru pripreme 154, 3-hidroksifenilborna kiselina (0.06 g, 0.40 mmol), 2M Na<2>CO<3>vodeni rastvor (0.4 mL) i Pd(PPh<3>)<4>(0.02 g, 0.02 mmol) su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.04 g, 30%).[1151] Preparation example 155: (3,5-difluoro-3'-hydroxy-biphenyl-4-ylsulfanyl)-acetic acid methyl ester [0438] (4-bromo-2,6-difluoro-phenylsulfanyl)-acetic acid methyl ester (0.12 g, 0.40 mmol) obtained in preparation example 154, 3-hydroxyphenylboronic acid (0.06 g, 0.40 mmol), 2M Na<2>CO<3>aqueous solution (0.4 mL) and Pd(PPh<3>)<4>(0.02 g, 0.02 mmol) were reacted in the same manner as in Preparation Example 13 to give the title compound (0.04 g, 30%).

[1152] <1>H-NMR (CDCl<3>) δ 7.31 (1H, t), 7.15 (2H, d), 7.11 (1H, m), 7.00 (1H, s), 6.88 (1H, m), 4.84 (1H, s), 3.69 (3H, s), 3.58 (2H, s).[1152] <1>H-NMR (CDCl<3>) δ 7.31 (1H, t), 7.15 (2H, d), 7.11 (1H, m), 7.00 (1H, s), 6.88 (1H, m), 4.84 (1H, s), 3.69 (3H, s), 3.58 (2H, s).

[1154] Primer pripreme 156: metil estar (3'-ciklopentiloksi-3,5-difluoro-bifenil-4-ilsulfanil)-sirćetne kiseline [0440] Metil estar (3,5-difluoro-3'-hidroksi-bifenil-4-ilsulfanil)-sirćetne kiseline (0.037 g, 0.12 mmol) dobijen u primeru pripreme 155, bromo-ciklopentan (0.02 mL) i Cs<2>CO<3>(0.12 g, 0.36 mmol) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.035 g, 77%).[1154] Preparation example 156: (3'-cyclopentyloxy-3,5-difluoro-biphenyl-4-ylsulfanyl)-acetic acid methyl ester [0440] (3,5-difluoro-3'-hydroxy-biphenyl-4-ylsulfanyl)-acetic acid methyl ester (0.037 g, 0.12 mmol) obtained in preparation example 155, bromo-cyclopentane (0.02 mL) and Cs<2>CO<3> (0.12 g, 0.36 mmol) were reacted in the same manner as in Step B of Preparation Example 44 to give the title compound (0.035 g, 77%).

[1155] <1>H-NMR (CDCl<3>) δ 7.33 (1H, t), 7.16 (2H, d), 7.07 (1H, m), 7.02 (1H, s), 6.90 (1H, m), 4.80 (1H, m), 3.69 (3H, s), 3.57 (2H, s), 1.92-1.80 (6H, m), 1.63 (2H, m).[1155] <1>H-NMR (CDCl<3>) δ 7.33 (1H, t), 7.16 (2H, d), 7.07 (1H, m), 7.02 (1H, s), 6.90 (1H, m), 4.80 (1H, m), 3.69 (3H, s), 3.57 (2H, s), 1.92-1.80 (6H, m), 1.63 (2H, m).

[1157] Primer pripreme 157: 2-(3'-ciklopentiloksi-3,5-difluoro-bifenil-4-ilsulfanil)-etanol[1157] Preparation example 157: 2-(3'-cyclopentyloxy-3,5-difluoro-biphenyl-4-ylsulfanyl)-ethanol

[1158] Nakon što je metil estar (3'-ciklopentiloksi-3,5-difluoro-bifenil-4-ilsulfanil)-sirćetne kiseline (0.034 g, 0.09 mmol) dobijen u primeru pripreme 156 rastvoren u THF-u (1 mL), dodat je LiBH<4>(0.09 g, 0.18 mmol) na 0°C, i mešavina je mešana na sobnoj temperaturi 2 sata. Reaktantu je dodata voda a zatim je ekstrahovan sa EtOAc. Organski sloj je izdvojen i osušen sa MgSO<4>, i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.027 g, 87 %).[1158] After (3'-cyclopentyloxy-3,5-difluoro-biphenyl-4-ylsulfanyl)-acetic acid methyl ester (0.034 g, 0.09 mmol) obtained in Preparation Example 156 was dissolved in THF (1 mL), LiBH<4> (0.09 g, 0.18 mmol) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. Water was added to the reactant and then extracted with EtOAc. The organic layer was separated and dried with MgSO<4> , and purified by column chromatography to give the title compound (0.027 g, 87 %).

[1159] <1>H-NMR (CDCl<3>) δ 7.33 (1H, t), 7.16 (2H, d), 7.07 (1H, m), 7.02 (1H, s), 6.91 (1H, m), 4.81 (1H, m), 3.65 (2H, q), 3.04 (2H, t), 2.24 (1H, t), 1.92-1.80 (6H, m), 1.63 (2H, m).[1159] <1>H-NMR (CDCl<3>) δ 7.33 (1H, t), 7.16 (2H, d), 7.07 (1H, m), 7.02 (1H, s), 6.91 (1H, m), 4.81 (1H, m), 3.65 (2H, q), 3.04 (2H, t), 2.24 (1H, t), 1.92-1.80 (6H, m), 1.63 (2H, m).

[1161] Primer pripreme 158: 4-(2-hloro-etilsulfanil)-3'-ciklopentiloksi-3,5-difluoro-bifenil[1161] Preparation example 158: 4-(2-chloro-ethylsulfanyl)-3'-cyclopentyloxy-3,5-difluoro-biphenyl

[1162] Nakon što je 2-(3'-ciklopentiloksi-3,5-difluoro-bifenil-4-ilsulfanil)-etanol (0.027 g, 0.08 mmol) dobijen u primeru pripreme 157 rastvoren u CH<3>CN (1 mL), dodat je SOCl<2>(0.01 mL, 0.15 mmol) na 0°C, mešavina je mešana na sobnoj temperaturi 1 sat. Reaktant je koncentrovan pod smanjenim pritiskom da bi se dobilo naslovno jedinjenje (0.028 g, 98 %).[1162] After 2-(3'-cyclopentyloxy-3,5-difluoro-biphenyl-4-ylsulfanyl)-ethanol (0.027 g, 0.08 mmol) obtained in preparation example 157 was dissolved in CH<3>CN (1 mL), SOCl<2> (0.01 mL, 0.15 mmol) was added at 0°C, the mixture was stirred at room temperature for 1 hour. The reactant was concentrated under reduced pressure to give the title compound (0.028 g, 98 %).

[1163] <1>H-NMR (CDCl<3>) δ 7.34 (1H, t), 7.17 (2H, d), 7.08 (1H, m), 7.03 (1H, s), 6.91 (1H, m), 4.81 (1H, m), 3.62 (2H, t), 3.17 (2H, t), 1.93-1.81 (6H, m), 1.64 (2H, m).[1163] <1>H-NMR (CDCl<3>) δ 7.34 (1H, t), 7.17 (2H, d), 7.08 (1H, m), 7.03 (1H, s), 6.91 (1H, m), 4.81 (1H, m), 3.62 (2H, t), 3.17 (2H, t), 1.93-1.81 (6H, m), 1.64 (2H, m).

[1165] Primer pripreme 159: etil estar 4-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline[1165] Preparation Example 159: 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester

[1166] Etil estar 4-(4-bromo-fenilsulfanil)-buterne kiseline (0.83 g, 2.7 mmol) dobijen u primeru pripreme 148, bis(pinakolato)dibor (0.76 g, 3.0 mmol), kalijumacetat (0.67 g, 6.8 mmol) i dihloro[1,1'-bis(difenilfosfino)ferocen]paladijum(II) (0.20 g, 0.27 mmol) su izreagovani na isti način kao u fazi A primera pripreme 1 da bi se dobilo naslovno jedinjenje (0.73 g, 75%).[1166] 4-(4-Bromo-phenylsulfanyl)-butyric acid ethyl ester (0.83 g, 2.7 mmol) obtained in Preparation Example 148, bis(pinacolato)diboron (0.76 g, 3.0 mmol), potassium acetate (0.67 g, 6.8 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (0.20 g, 0.27 mmol) were reacted in the same manner as in Step A of Preparative Example 1 to give the title compound (0.73 g, 75%).

[1167] <1>H-NMR (CDCl<3>) δ 7.70 (2H, d), 7.27 (2H, d), 4.11 (2H, q), 2.99 (2H, t), 2.44 (2H, t), 1.96 (2H, m), 1.32 (12H, s), 1.24 (3H, t).[1167] <1>H-NMR (CDCl<3>) δ 7.70 (2H, d), 7.27 (2H, d), 4.11 (2H, q), 2.99 (2H, t), 2.44 (2H, t), 1.96 (2H, m), 1.32 (12H, s), 1.24 (3H, t).

[1169] Primer pripreme 160: etil estar 4-(4-metoksi-benzilsulfanil)-buterne kiseline[1169] Preparation example 160: 4-(4-methoxy-benzylsulfanyl)-butyric acid ethyl ester

[1170] (4-metoksi-fenil)-metantiol (0.5 g, 3.24 mmol), NaH (60% u mineralnom ulju, 0.13 g, 3.24 mmol) i etil estar 4-bromo-buterne kiseline (0.51 mL, 3.57 mmol) su izreagovani na isti način kao u primeru pripreme 12 da bi se dobilo naslovno jedinjenje (0.70 g, 80 %).[1170] (4-Methoxy-phenyl)-methanethiol (0.5 g, 3.24 mmol), NaH (60% in mineral oil, 0.13 g, 3.24 mmol) and 4-bromo-butyric acid ethyl ester (0.51 mL, 3.57 mmol) were reacted in the same manner as in Preparation Example 12 to give the title compound (0.70 g, 80%).

[1171] <1>H-NMR (CDCl<3>) δ 7.22 (2H, d), 6.83 (2H, d), 4.12 (2H, q), 3.79 (3H, s), 3.65 (2H, s), 2.43 (2H, t), 2.38 (2H, t), 1.87 (2H, m), 1.24 (3H, t).[1171] <1>H-NMR (CDCl<3>) δ 7.22 (2H, d), 6.83 (2H, d), 4.12 (2H, q), 3.79 (3H, s), 3.65 (2H, s), 2.43 (2H, t), 2.38 (2H, t), 1.87 (2H, m), 1.24 (3H, t).

[1173] Primer pripreme 161: etil estar 4-merkapto-buterne kiseline[1173] Preparation example 161: 4-mercapto-butyric acid ethyl ester

[1174] Nakon što je etil estar 4-(4-metoksi-benzilsulfanil)-buterne kiseline (0.7 g, 2.61 mmol) dobijen u primeru pripreme 160 rastvoren u TFA-u (5 mL), dodati su anizol (1.5 mL) i trifluorometansulfonska kiselina (0.5 mL), i mešavina je mešana na sobnoj temperaturi 1 sat. Reaktant je dodat sa[1174] After 4-(4-methoxy-benzylsulfanyl)-butyric acid ethyl ester (0.7 g, 2.61 mmol) obtained in Preparation Example 160 was dissolved in TFA (5 mL), anisole (1.5 mL) and trifluoromethanesulfonic acid (0.5 mL) were added, and the mixture was stirred at room temperature for 1 hour. The reactant was added with

[1175] NaHCO<3>vodenim rastvorom a zatim je ekstrahovan sa EtOAc. Organski sloj je izdvojen i osušen sa MgSO<4>, i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.37 g, 95 %).[1175] with NaHCO<3>aqueous solution and then extracted with EtOAc. The organic layer was separated and dried with MgSO<4> , and purified by column chromatography to give the title compound (0.37 g, 95 %).

[1176] <1>H-NMR (CDCl<3>) δ 4.13 (2H, q), 3.11 (2H, t), 2.41 (2H, t), 1.99 (2H, m), 1.26 (3H, t).[1176] <1>H-NMR (CDCl<3>) δ 4.13 (2H, q), 3.11 (2H, t), 2.41 (2H, t), 1.99 (2H, m), 1.26 (3H, t).

[1178] Primer pripreme 162: 3',4',5'-trifluoro-bifenil-3-ol[1178] Preparation Example 162: 3',4',5'-trifluoro-biphenyl-3-ol

[1179] 5-bromo-1,2,3-trifluoro-benzen (0.20 g, 0.95 mmol), 3-hidroksifenilborna kiselina (0.13 g, 0.95 mmol), 2M Na<2>CO<3>vodeni rastvor (0.9 mL) i Pd(PPh<3>)<4>(0.055 g, 0.05 mmol) su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.18 g, 83%).[1179] 5-bromo-1,2,3-trifluoro-benzene (0.20 g, 0.95 mmol), 3-hydroxyphenylboronic acid (0.13 g, 0.95 mmol), 2M Na<2>CO<3>aqueous solution (0.9 mL) and Pd(PPh<3>)<4> (0.055 g, 0.05 mmol) were reacted in the same manner as in the preparation example. 13 to give the title compound (0.18 g, 83%).

[1180] <1>H-NMR (CDCl<3>) δ 7.30 (1H, t), 7.17 (2H, m), 7.06 (1H, m), 6.95 (1H, s), 6.85 (1H, m), 4.91 (1H, s).[1180] <1>H-NMR (CDCl<3>) δ 7.30 (1H, t), 7.17 (2H, m), 7.06 (1H, m), 6.95 (1H, s), 6.85 (1H, m), 4.91 (1H, s).

[1182] Primer pripreme 163: 3'-ciklobutoksi-3,4,5-trifluoro-bifenil[1182] Preparation example 163: 3'-cyclobutoxy-3,4,5-trifluoro-biphenyl

[1183] 3',4',5'-trifluoro-bifenil-3-ol (0.05 g, 0.22 mmol) dobijen u primeru pripreme 162, bromociklobutan (0.03 mL) i Cs<2>CO<3>(0.22 g) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.04 g, 64%).[1183] 3',4',5'-trifluoro-biphenyl-3-ol (0.05 g, 0.22 mmol) obtained in Preparative Example 162, bromocyclobutane (0.03 mL) and Cs<2>CO<3> (0.22 g) were reacted in the same manner as in Step B of Preparative Example 44 to give the title compound (0.04 g, 64%).

[1184] <1>H-NMR (CDCl<3>) δ 7.32 (1H, t), 7.15 (2H, m), 7.04 (1H, m), 6.92 (1H, s), 6.82 (1H, m), 4.68 (1H, m), 2.46 (2H, m), 2.20 (2H, m), 1.88 (1H, m), 1.71 (1H, m).[1184] <1>H-NMR (CDCl<3>) δ 7.32 (1H, t), 7.15 (2H, m), 7.04 (1H, m), 6.92 (1H, s), 6.82 (1H, m), 4.68 (1H, m), 2.46 (2H, m), 2.20 (2H, m), 1.88 (1H, m), 1.71 (1H, m).

[1186] Primer pripreme 164: 3,4,5-trifluoro-3'-izopropoksi-bifenil[1186] Preparation Example 164: 3,4,5-trifluoro-3'-isopropoxy-biphenyl

[1187] 3',4',5'-trifluoro-bifenil-3-ol (0.05 g, 0.22 mmol) dobijen u primeru pripreme 162, 2-bromopropan (0.03 mL) i Cs<2>CO<3>(0.22 g) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.06 g, 100%).[1187] 3',4',5'-trifluoro-biphenyl-3-ol (0.05 g, 0.22 mmol) obtained in Preparative Example 162, 2-bromopropane (0.03 mL) and Cs<2>CO<3> (0.22 g) were reacted in the same manner as in Step B of Preparative Example 44 to give the title compound (0.06 g, 100%).

[1188] <1>H-NMR (CDCl<3>) δ 7.32 (1H, t), 7.18 (2H, m), 7.03 (1H, m), 6.99 (1H, s), 6.89 (1H, m), 4.60 (1H, m), 1.35 (6H, d).[1188] <1>H-NMR (CDCl<3>) δ 7.32 (1H, t), 7.18 (2H, m), 7.03 (1H, m), 6.99 (1H, s), 6.89 (1H, m), 4.60 (1H, m), 1.35 (6H, d).

[1190] Primer pripreme 165: 4,4,5,5-tetrametil-2-(3,4,5-trifluoro-fenil)-[1,3,2]dioksaborolan[1190] Preparation Example 165: 4,4,5,5-tetramethyl-2-(3,4,5-trifluoro-phenyl)-[1,3,2]dioxaborolane

[1191] 5-bromo-1,2,3-trifluoro-benzen (0.50 g, 2.37 mmol), bis(pinakolato)dibor (0.66 g, 2.61 mmol), kalijumacetat (0.58 g, 5.92 mmol) i trans-dihlorobis(trifenilfosfin)paladijum(II) (0.17 g, 0.24 mmol) su izreagovani na isti način kao u fazi A primera pripreme 1 da bi se dobilo naslovno jedinjenje (0.24 g, 39%).[1191] 5-bromo-1,2,3-trifluoro-benzene (0.50 g, 2.37 mmol), bis(pinacolato)diboron (0.66 g, 2.61 mmol), potassium acetate (0.58 g, 5.92 mmol) and trans-dichlorobis(triphenylphosphine)palladium(II) (0.17 g, 0.24 mmol) were reacted in the same manner as in step A. of preparation example 1 to give the title compound (0.24 g, 39%).

[1192] <1>H-NMR (CDCl<3>) δ 7.36 (2H, m), 1.35 (12H, s).[1192] <1>H-NMR (CDCl<3>) δ 7.36 (2H, m), 1.35 (12H, s).

[1194] Primer pripreme 166: 2-propoksi-6-(3,4,5-trifluoro-fenil)-piridin[1194] Preparation Example 166: 2-propoxy-6-(3,4,5-trifluoro-phenyl)-pyridine

[1195] 4,4,5,5-tetrametil-2-(3,4,5-trifluoro-fenil)-[1,3,2]dioksaborolan (0.03 g, 0.12 mmol) dobijen u primeru pripreme 165, 2-bromo-6-propoksi-piridin (0.027, 0.13 mmol) dobijen u primeru pripreme 227, 2M Na<2>CO<3>vodeni rastvor (0.2 mL) i Pd(PPh<3>)<4>(0.007 g, 0.006 mmol) su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.023 g, 74%).[1195] 4,4,5,5-tetramethyl-2-(3,4,5-trifluoro-phenyl)-[1,3,2]dioxaborolane (0.03 g, 0.12 mmol) obtained in preparation example 165, 2-bromo-6-propoxy-pyridine (0.027, 0.13 mmol) obtained in preparation example 227, 2M Na<2>CO<3>aqueous solution (0.2 mL) and Pd(PPh<3>)<4> (0.007 g, 0.006 mmol) were reacted in the same manner as in Preparation Example 13 to give the title compound (0.023 g, 74%).

[1196] <1>H-NMR (CDCl<3>) δ 7.64 (3H, m), 7.23 (1H, d), 6.71 (1H, d), 4.35 (2H, t), 1.84 (2H, m), 1.05 (3H, t).[1196] <1>H-NMR (CDCl<3>) δ 7.64 (3H, m), 7.23 (1H, d), 6.71 (1H, d), 4.35 (2H, t), 1.84 (2H, m), 1.05 (3H, t).

[1198] Primer pripreme 167: 2-izopropoksi-6-(3,4,5-trifluoro-fenil)-piridin[1198] Preparation Example 167: 2-isopropoxy-6-(3,4,5-trifluoro-phenyl)-pyridine

[1199] 4,4,5,5-tetrametil-2-(3,4,5-trifluoro-fenil)-[1,3,2]dioksaborolan (0.054 g, 0.21 mmol) dobijen u primeru pripreme 165, 2-bromo-6-izopropoksi-piridin (0.050 g, 0.23 mmol) dobijen u primeru pripreme 228, 2M Na<2>CO<3>vodeni rastvor (0.3 mL) i Pd(PPh<3>)<4>(0.012 g, 0.01 mmol) su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.02 g, 32%).[1199] 4,4,5,5-tetramethyl-2-(3,4,5-trifluoro-phenyl)-[1,3,2]dioxaborolane (0.054 g, 0.21 mmol) obtained in preparation example 165, 2-bromo-6-isopropoxy-pyridine (0.050 g, 0.23 mmol) obtained in preparation example 228, 2M Na<2>CO<3>aqueous solution (0.3 mL) and Pd(PPh<3>)<4> (0.012 g, 0.01 mmol) were reacted in the same manner as in Preparation Example 13 to give the title compound (0.02 g, 32%).

[1200] <1>H-NMR (CDCl<3>) δ 7.63 (3H, m), 7.22 (1H, d), 6.67 (1H, d), 5.44 (1H, m), 1.40 (6H, d).[1200] <1>H-NMR (CDCl<3>) δ 7.63 (3H, m), 7.22 (1H, d), 6.67 (1H, d), 5.44 (1H, m), 1.40 (6H, d).

[1202] Primer pripreme 168: 4-bromo-2,6-difluoro-benzentiol[1202] Preparation Example 168: 4-bromo-2,6-difluoro-benzenethiol

[1203] Faza A: 4-bromo-2,6-difluoro-benzensulfonil hlorid[1203] Phase A: 4-bromo-2,6-difluoro-benzenesulfonyl chloride

[1204] Nakon što je CuCl<2>(0.77 g, 5.77 mmol) rastvoren u vodi (200 mL), dodat je SOCl<2>(29 mL, 0.40 mol) na 0°C, i mešavina je mešana na sobnoj temperaturi 18 sati. Zatim, 4-bromo-2,6-difluoroanilin (20 g, 0.096 mol) je rastvoren u HCl (240 mL) i vodi (900 mL), i tome je dodat rastvor NaNO<2>(7 g, 0.10 mol) rastvoren u vodi (200 mL) na 0°C. Mešavina je dodata sa pripremljenim rastvorom tionilhlorida, i izreagovana 1 sat da bi se dobio čvrst oblik naslovnog jedinjenja (24 g, 85 %).[1204] After CuCl<2>(0.77 g, 5.77 mmol) was dissolved in water (200 mL), SOCl<2>(29 mL, 0.40 mol) was added at 0°C, and the mixture was stirred at room temperature for 18 hours. Next, 4-bromo-2,6-difluoroaniline (20 g, 0.096 mol) was dissolved in HCl (240 mL) and water (900 mL), and a solution of NaNO<2> (7 g, 0.10 mol) dissolved in water (200 mL) was added at 0°C. The mixture was added with the prepared thionyl chloride solution, and reacted for 1 hour to give the title compound as a solid (24 g, 85 %).

[1206] Faza B: 4-bromo-2,6-difluoro-benzentiol[1206] Phase B: 4-bromo-2,6-difluoro-benzenethiol

[1207] Nakon što je 4-bromo-2,6-difluoro-benzensulfonil hlorid (24 g, 0.08 mol) dobijen u fazi A rastvoren u THF-u (270 mL), dodat je PPh<3>(75 g, 0.28 mol). Zatim je mešavina mešana na sobnoj temperaturi 15 minuta, dodata joj je voda, i mešana je na sobnoj temperaturi 18 sati. Reaktantu je dodata voda a zatim je ekstrahovan sa EtOAc. Organski sloj je izdvojen i osušen sa MgSO<4>, i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (15 g, 83 %).[1207] After the 4-bromo-2,6-difluoro-benzenesulfonyl chloride (24 g, 0.08 mol) obtained in phase A was dissolved in THF (270 mL), PPh<3> (75 g, 0.28 mol) was added. The mixture was then stirred at room temperature for 15 minutes, water was added, and it was stirred at room temperature for 18 hours. Water was added to the reactant and then extracted with EtOAc. The organic layer was separated and dried with MgSO4 , and purified by column chromatography to give the title compound (15 g, 83 %).

[1208] <1>H-NMR (CDCl<3>) δ 7.10 (2H, d), 3.58 (1H, s).[1208] <1>H-NMR (CDCl<3>) δ 7.10 (2H, d), 3.58 (1H, s).

[1210] Primer pripreme 169: etil estar 4-(4-bromo-2,6-difluoro-fenilsulfanil)-buterne kiseline[1210] Preparation example 169: 4-(4-bromo-2,6-difluoro-phenylsulfanyl)-butyric acid ethyl ester

[1211] 4-bromo-2,6-difluoro-benzentiol (15 g, 0.066 mol) dobijen u primeru pripreme 168, NaH (60% u mineralnom ulju, 2.6 g, 0.066 mol) i etil estar 4-bromo-buterne kiseline (10 mL, 0.073 mol) su izreagovani na isti način kao u primeru pripreme 12 da bi se dobilo naslovno jedinjenje (18.56 g, 82 %).[1211] 4-Bromo-2,6-difluoro-benzenethiol (15 g, 0.066 mol) obtained in Preparative Example 168, NaH (60% in mineral oil, 2.6 g, 0.066 mol) and 4-bromo-butyric acid ethyl ester (10 mL, 0.073 mol) were reacted in the same manner as in Preparative Example 12 to give the title compound. (18.56 g, 82 %).

[1212] <1>H-NMR (CDCl<3>) δ 7.11 (2H, d), 4.11 (2H, q), 2.90 (2H, t), 2.43 (2H, t), 1.82 (2H, m), 1.24 (3H, t).[1212] <1>H-NMR (CDCl<3>) δ 7.11 (2H, d), 4.11 (2H, q), 2.90 (2H, t), 2.43 (2H, t), 1.82 (2H, m), 1.24 (3H, t).

[1214] Primer pripreme 170: etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline[1214] Preparation Example 170: 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester

[1215] Etil estar 4-(4-bromo-2,6-difluoro-fenilsulfanil)-buterne kiseline (11.6 g, 0.034 mol) dobijen u primeru pripreme 169, bis(pinakolato)dibor (9.5 g, 0.038 mol), kalijumacetat (8.4 g, 0.085 mol) i dihloro[1,1'-bis(difenilfosfino)ferocen]paladijum(II) (2.5 g, 0.003 mol) su izreagovani na isti način kao u fazi A primera pripreme 1 da bi se dobilo naslovno jedinjenje (10.6 g, 80%).[1215] 4-(4-Bromo-2,6-difluoro-phenylsulfanyl)-butyric acid ethyl ester (11.6 g, 0.034 mol) obtained in Preparation Example 169, bis(pinacolato)diboron (9.5 g, 0.038 mol), potassium acetate (8.4 g, 0.085 mol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (2.5 g, 0.003 mol) were reacted in the same manner as in Step A of Preparation Example 1 to give the title compound (10.6 g, 80%).

[1216] <1>H-NMR (CDCl<3>) δ 7.30 (2H, d), 4.09 (2H, q), 2.94 (2H, t), 2.43 (2H, t), 1.83 (2H, m), 1.33 (12H, s), 1.22 (3H, t).[1216] <1>H-NMR (CDCl<3>) δ 7.30 (2H, d), 4.09 (2H, q), 2.94 (2H, t), 2.43 (2H, t), 1.83 (2H, m), 1.33 (12H, s), 1.22 (3H, t).

[1218] Primer pripreme 171: 2-propoksi-3-(3,4,5-trifluoro-fenil)-piridin[1218] Preparation example 171: 2-propoxy-3-(3,4,5-trifluoro-phenyl)-pyridine

[1219] 4,4,5,5-tetrametil-2-(3,4,5-trifluoro-fenil)-[1,3,2]dioksaborolan (0.05 g, 0.19 mmol) dobijen u primeru pripreme 165, 3-jodo-2-propoksi-piridin (0.056 g, 0.21 mmol) dobijen u primeru pripreme 202, 2M Na<2>CO<3>vodeni rastvor (0.3 mL) i Pd(PPh<3>)<4>(0.011 g, 0.01 mmol) su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.02 g, 43%).[1219] 4,4,5,5-tetramethyl-2-(3,4,5-trifluoro-phenyl)-[1,3,2]dioxaborolane (0.05 g, 0.19 mmol) obtained in preparation example 165, 3-iodo-2-propoxy-pyridine (0.056 g, 0.21 mmol) obtained in preparation example 202, 2M Na<2>CO<3>aqueous solution (0.3 mL) and Pd(PPh<3>)<4> (0.011 g, 0.01 mmol) were reacted in the same manner as in Preparation Example 13 to give the title compound (0.02 g, 43%).

[1220] <1>H-NMR (CDCl<3>) δ 8.15 (1H, m), 7.55 (1H, m), 7.21 (2H, m), 6.95 (1H, m), 4.31 (2H, t), 1.77 (2H, m), 1.00 (3H, t).[1220] <1>H-NMR (CDCl<3>) δ 8.15 (1H, m), 7.55 (1H, m), 7.21 (2H, m), 6.95 (1H, m), 4.31 (2H, t), 1.77 (2H, m), 1.00 (3H, t).

[1222] Primer pripreme 172: 2-izopropilsulfanil-6-(3,4,5-trifluoro-fenil)-piridin[1222] Preparation example 172: 2-isopropylsulfanyl-6-(3,4,5-trifluoro-phenyl)-pyridine

[1223] 4,4,5,5-tetrametil-2-(3,4,5-trifluoro-fenil)-[1,3,2]dioksaborolan (0.050 g, 0.19 mmol) dobijen u primeru pripreme 165, 2-bromo-6-izopropilsulfanil-piridin (0.049 g, 0.21 mmol) dobijen u primeru pripreme 201, 2M Na<2>CO<3>vodeni rastvor (0.3 mL) i Pd(PPh<3>)<4>(0.011 g, 0.01 mmol) su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.035 g, 64%).[1223] 4,4,5,5-tetramethyl-2-(3,4,5-trifluoro-phenyl)-[1,3,2]dioxaborolane (0.050 g, 0.19 mmol) obtained in preparation example 165, 2-bromo-6-isopropylsulfanyl-pyridine (0.049 g, 0.21 mmol) obtained in preparation example 201, 2M Na<2>CO<3>aqueous solution (0.3 mL) and Pd(PPh<3>)<4> (0.011 g, 0.01 mmol) were reacted in the same manner as in Preparation Example 13 to give the title compound (0.035 g, 64%).

[1224] <1>H-NMR (CDCl<3>) δ 7.67 (2H, m), 7.53 (1H, t), 7.32 (1H, d), 7.12 (1H, d), 4.11 (1H, m), 1.46 (6H, d).[1224] <1>H-NMR (CDCl<3>) δ 7.67 (2H, m), 7.53 (1H, t), 7.32 (1H, d), 7.12 (1H, d), 4.11 (1H, m), 1.46 (6H, d).

[1225] Primer pripreme 173: 2-propilsulfanil-6-(3,4,5-trifluoro-fenil)-piridin[1225] Preparation example 173: 2-propylsulfanyl-6-(3,4,5-trifluoro-phenyl)-pyridine

[1226] 4,4,5,5-tetrametil-2-(3,4,5-trifluoro-fenil)-[1,3,2]dioksaborolan (0.050 g, 0.19 mmol) dobijen u primeru pripreme 165, 2-bromo-6-propilsulfanil-piridin (0.049 g, 0.21 mmol) dobijen u primeru pripreme 229, 2M Na<2>CO<3>vodeni rastvor (0.3 mL) i Pd(PPh<3>)<4>(0.011 g, 0.01 mmol) su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.03 g, 57%).[1226] 4,4,5,5-tetramethyl-2-(3,4,5-trifluoro-phenyl)-[1,3,2]dioxaborolane (0.050 g, 0.19 mmol) obtained in preparation example 165, 2-bromo-6-propylsulfanyl-pyridine (0.049 g, 0.21 mmol) obtained in preparation example 229, 2M Na<2>CO<3>aqueous solution (0.3 mL) and Pd(PPh<3>)<4> (0.011 g, 0.01 mmol) were reacted in the same manner as in Preparation Example 13 to give the title compound (0.03 g, 57%).

[1227] <1>H-NMR (CDCl<3>) δ 7.66 (2H, m), 7.53 (1H, t), 7.32 (1H, d), 7.14 (1H, d), 3.22 (2H, t), 1.80 (2H, m), 1.09 (3H, t).[1227] <1>H-NMR (CDCl<3>) δ 7.66 (2H, m), 7.53 (1H, t), 7.32 (1H, d), 7.14 (1H, d), 3.22 (2H, t), 1.80 (2H, m), 1.09 (3H, t).

[1229] Primer pripreme 174: 2-ciklobutilsulfanil-3-(3,4,5-trifluoro-fenil)-piridin[1229] Preparation example 174: 2-cyclobutylsulfanyl-3-(3,4,5-trifluoro-phenyl)-pyridine

[1230] 4,4,5,5-tetrametil-2-(3,4,5-trifluoro-fenil)-[1,3,2]dioksaborolan (0.050 g, 0.19 mmol) dobijen u primeru pripreme 165, 2-ciklobutilsulfanil-3-jodo-piridin (0.062 g, 0.21 mmol) dobijen u primeru pripreme 44, 2M Na<2>CO<3>vodeni rastvor (0.3 mL) i Pd(PPh<3>)<4>(0.011 g, 0.01 mmol) su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.056 g, 98%).[1230] 4,4,5,5-tetramethyl-2-(3,4,5-trifluoro-phenyl)-[1,3,2]dioxaborolane (0.050 g, 0.19 mmol) obtained in preparation example 165, 2-cyclobutylsulfanyl-3-iodo-pyridine (0.062 g, 0.21 mmol) obtained in preparation example 44, 2M Na<2>CO<3>aqueous solution (0.3 mL) and Pd(PPh<3>)<4> (0.011 g, 0.01 mmol) were reacted in the same manner as in Preparation Example 13 to give the title compound (0.056 g, 98%).

[1231] <1>H-NMR (CDCl<3>) δ 8.43 (1H, m), 7.33 (1H, m), 7.04 (3H, m), 4.43 (1H, m), 2.52 (2H, m), 2.05 (4H, m).[1231] <1>H-NMR (CDCl<3>) δ 8.43 (1H, m), 7.33 (1H, m), 7.04 (3H, m), 4.43 (1H, m), 2.52 (2H, m), 2.05 (4H, m).

[1233] Primer pripreme 175: 2-ciklobutoksi-3-(3,4,5-trifluoro-fenil)-piridin[1233] Preparation Example 175: 2-cyclobutoxy-3-(3,4,5-trifluoro-phenyl)-pyridine

[1234] 4,4,5,5-tetrametil-2-(3,4,5-trifluoro-fenil)-[1,3,2]dioksaborolan (0.050 g, 0.19 mmol) dobijen u primeru pripreme 165, 2-ciklobutoksi-3-jodo-piridin (0.059 g, 0.21 mmol) dobijen u primeru pripreme 200, 2M Na<2>CO<3>vodeni rastvor (0.3 mL) i Pd(PPh<3>)<4>(0.011 g, 0.01 mmol) su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.01 g, 18%).[1234] 4,4,5,5-tetramethyl-2-(3,4,5-trifluoro-phenyl)-[1,3,2]dioxaborolane (0.050 g, 0.19 mmol) obtained in preparation example 165, 2-cyclobutoxy-3-iodo-pyridine (0.059 g, 0.21 mmol) obtained in preparation example 200, 2M Na<2>CO<3>aqueous solution (0.3 mL) and Pd(PPh<3>)<4> (0.011 g, 0.01 mmol) were reacted in the same manner as in Preparation Example 13 to give the title compound (0.01 g, 18%).

[1235] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.55 (1H, m), 7.25 (2H, m), 6.93 (1H, m), 5.28 (1H, m), 2.46 (2H, m), 2.12 (2H, m), 1.82 (1H, m), 1.68 (1H, m).[1235] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.55 (1H, m), 7.25 (2H, m), 6.93 (1H, m), 5.28 (1H, m), 2.46 (2H, m), 2.12 (2H, m), 1.82 (1H, m), 1.68 (1H, m).

[1237] Primer pripreme 176: 2-ciklopentilsulfanil-3-(3,4,5-trifluoro-fenil)-piridin[1237] Preparation example 176: 2-cyclopentylsulfanyl-3-(3,4,5-trifluoro-phenyl)-pyridine

[1238] 4,4,5,5-tetrametil-2-(3,4,5-trifluoro-fenil)-[1,3,2]dioksaborolan (0.050 g, 0.19 mmol) dobijen u primeru pripreme 165, 2-ciklopentilsulfanil-3-jodo-piridin (0.065 g, 0.21 mmol) dobijen u primeru pripreme 39, 2M Na<2>CO<3>vodeni rastvor (0.3 mL) i Pd(PPh<3>)<4>(0.011 g, 0.01 mmol) su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.02 g, 33%).[1238] 4,4,5,5-tetramethyl-2-(3,4,5-trifluoro-phenyl)-[1,3,2]dioxaborolane (0.050 g, 0.19 mmol) obtained in preparation example 165, 2-cyclopentylsulfanyl-3-iodo-pyridine (0.065 g, 0.21 mmol) obtained in preparation example 39, 2M Na<2>CO<3>aqueous solution (0.3 mL) and Pd(PPh<3>)<4> (0.011 g, 0.01 mmol) were reacted in the same manner as in Preparation Example 13 to give the title compound (0.02 g, 33%).

[1239] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.31 (1H, m), 7.05 (3H, m), 4.10 (1H, m), 2.19 (2H, m), 1.72-1.52 (6H, m).[1239] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.31 (1H, m), 7.05 (3H, m), 4.10 (1H, m), 2.19 (2H, m), 1.72-1.52 (6H, m).

[1241] Primer pripreme 177: 4-bromo-2-fluoro-benzensulfonil hlorid[1241] Preparation Example 177: 4-bromo-2-fluoro-benzenesulfonyl chloride

[1242] 4-bromo-2-fluoro-anilin (1 g, 5.26 mmol) je izreagovan na isti način kao u fazi A primera pripreme 168 da bi se dobilo naslovno jedinjenje (0.49 g, 34%).[1242] 4-Bromo-2-fluoro-aniline (1 g, 5.26 mmol) was reacted in the same manner as in Step A of Preparative Example 168 to give the title compound (0.49 g, 34%).

[1243] <1>H-NMR (CDCl<3>) δ 7.85 (1H, m), 7.55 (2H, m).[1243] <1>H-NMR (CDCl<3>) δ 7.85 (1H, m), 7.55 (2H, m).

[1244] Primer pripreme 178: 4-bromo-2-fluoro-benzentiol[1244] Preparation example 178: 4-bromo-2-fluoro-benzenethiol

[1245] 4-bromo-2-fluoro-benzensulfonil hlorid (0.49 g, 1.79 mmol) dobijen u primeru pripreme 177 je izreagovan na isti način kao u fazi B primera pripreme 168 da bi se dobilo naslovno jedinjenje (0.37 g, 99%).[1245] 4-Bromo-2-fluoro-benzenesulfonyl chloride (0.49 g, 1.79 mmol) obtained in Preparative Example 177 was reacted in the same manner as in Step B of Preparative Example 168 to give the title compound (0.37 g, 99%).

[1246] <1>H-NMR (CDCl<3>) δ 7.23 (1H, m), 7.16 (2H, m), 3.57 (1H, s).[1246] <1>H-NMR (CDCl<3>) δ 7.23 (1H, m), 7.16 (2H, m), 3.57 (1H, s).

[1248] Primer pripreme 179: etil estar 4-(4-bromo-2-fluoro-fenilsulfanil)-buterne kiseline[1248] Preparation example 179: 4-(4-bromo-2-fluoro-phenylsulfanyl)-butyric acid ethyl ester

[1249] 4-bromo-2-fluoro-benzentiol (0.37 g, 1.81 mmol) dobijen u primeru pripreme 178, NaH (60% u mineralnom ulju, 0.07 g, 1.81 mmol) i etil estar 4-bromo-buterne kiseline (0.28 mL, 1.99 mmol) su izreagovani na isti način kao u primeru pripreme 12 da bi se dobilo naslovno jedinjenje (0.43 g, 75 %).[1249] 4-Bromo-2-fluoro-benzenethiol (0.37 g, 1.81 mmol) obtained in Preparative Example 178, NaH (60% in mineral oil, 0.07 g, 1.81 mmol) and 4-bromo-butyric acid ethyl ester (0.28 mL, 1.99 mmol) were reacted in the same manner as in Preparative Example 12 to give the title compound. (0.43 g, 75 %).

[1250] <1>H-NMR (CDCl<3>) δ 7.23 (3H, m), 4.12 (2H, q), 2.92 (2H, t), 2.44 (2H, t), 1.90 (2H, m), 1.25 (3H, t).[1250] <1>H-NMR (CDCl<3>) δ 7.23 (3H, m), 4.12 (2H, q), 2.92 (2H, t), 2.44 (2H, t), 1.90 (2H, m), 1.25 (3H, t).

[1252] Primer pripreme 180: etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline[1252] Preparation Example 180: 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester

[1253] Etil estar 4-(4-bromo-2-fluoro-fenilsulfanil)-buterne kiseline (0.43 g, 1.36 mmol) dobijen u primeru pripreme 179, bis(pinakolato)dibor (0.34 g, 1.50 mmol), kalijumacetat (0.33 g, 3.4 mmol) i dihloro[1,1'-bis(difenilfosfino)ferocen]paladijum(II) (0.10 g, 0.14 mmol) su izreagovani na isti način kao u fazi A primera pripreme 1 da bi se dobilo naslovno jedinjenje (0.27 g, 53%).[1253] 4-(4-bromo-2-fluoro-phenylsulfanyl)-butyric acid ethyl ester (0.43 g, 1.36 mmol) obtained in Preparation Example 179, bis(pinacolato)diboron (0.34 g, 1.50 mmol), potassium acetate (0.33 g, 3.4 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (0.10 g, 0.14 mmol) were reacted in the same manner as in Step A of Preparation Example 1 to give the title compound (0.27 g, 53%).

[1254] <1>H-NMR (CDCl<3>) δ 7.50 (1H, d), 7.43 (1H, d), 7.32 (1H, t), 4.11 (2H, q), 2.98 (2H, t), 2.45 (2H, t), 1.93 (2H, m), 1.33 (12H, s), 1.24 (3H, t).[1254] <1>H-NMR (CDCl<3>) δ 7.50 (1H, d), 7.43 (1H, d), 7.32 (1H, t), 4.11 (2H, q), 2.98 (2H, t), 2.45 (2H, t), 1.93 (2H, m), 1.33 (12H, s), 1.24 (3H, t).

[1256] Primer pripreme 181: 2-ciklobutoksi-6-(3,4,5-trifluoro-fenil)-piridin[1256] Preparation Example 181: 2-cyclobutoxy-6-(3,4,5-trifluoro-phenyl)-pyridine

[1257] 4,4,5,5-tetrametil-2-(3,4,5-trifluoro-fenil)-[1,3,2]dioksaborolan (0.050 g, 0.19 mmol) dobijen u primeru pripreme 165, 2-bromo-6-(ciklobutoksi)-piridin (0.044 g, 0.19 mmol) dobijen u primeru pripreme 230, 2M Na<2>CO<3>vodeni rastvor (0.3 mL) i Pd(PPh<3>)<4>(0.011 g, 0.01 mmol) su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.03 g, 49%).[1257] 4,4,5,5-tetramethyl-2-(3,4,5-trifluoro-phenyl)-[1,3,2]dioxaborolane (0.050 g, 0.19 mmol) obtained in preparation example 165, 2-bromo-6-(cyclobutoxy)-pyridine (0.044 g, 0.19 mmol) obtained in preparation example 230, 2M Na<2>CO<3>aqueous solution (0.3 mL) and Pd(PPh<3>)<4> (0.011 g, 0.01 mmol) were reacted in the same manner as in Preparation Example 13 to give the title compound (0.03 g, 49%).

[1258] <1>H-NMR (CDCl<3>) δ 7.64 (3H, m), 7.22 (1H, d), 6.67 (1H, d), 5.25 (1H, m), 2.52 (2H, m), 2.19 (2H, m), 1.87 (1H, m), 1.76 (1H, m).[1258] <1>H-NMR (CDCl<3>) δ 7.64 (3H, m), 7.22 (1H, d), 6.67 (1H, d), 5.25 (1H, m), 2.52 (2H, m), 2.19 (2H, m), 1.87 (1H, m), 1.76 (1H, m).

[1260] Primer pripreme 182: 2-ciklopentiloksi-6-(3,4,5-trifluoro-fenil)-piridin[1260] Preparation Example 182: 2-cyclopentyloxy-6-(3,4,5-trifluoro-phenyl)-pyridine

[1261] 4,4,5,5-tetrametil-2-(3,4,5-trifluoro-fenil)-[1,3,2]dioksaborolan (0.050 g, 0.19 mmol) dobijen u primeru pripreme 165, 2-bromo-6-(ciklopentoksi)piridin (0.047 g, 0.19 mmol) dobijen u primeru pripreme 231, 2M Na<2>CO<3>vodeni rastvor (0.3 mL) i Pd(PPh<3>)<4>(0.011 g, 0.01 mmol) su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.035 g, 62%).[1261] 4,4,5,5-tetramethyl-2-(3,4,5-trifluoro-phenyl)-[1,3,2]dioxaborolane (0.050 g, 0.19 mmol) obtained in preparation example 165, 2-bromo-6-(cyclopentoxy)pyridine (0.047 g, 0.19 mmol) obtained in preparation example 231, 2M Na<2>CO<3>aqueous solution (0.3 mL) and Pd(PPh<3>)<4> (0.011 g, 0.01 mmol) were reacted in the same manner as in Preparation Example 13 to give the title compound (0.035 g, 62%).

[1262] <1>H-NMR (CDCl<3>) δ 7.67-7.59 (3H, m), 7.19 (1H, d), 6.67 (1H, d), 5.49 (1H, m), 2.03 (2H, m), 1.85 (4H, m), 1.65 (2H, m).[1262] <1>H-NMR (CDCl<3>) δ 7.67-7.59 (3H, m), 7.19 (1H, d), 6.67 (1H, d), 5.49 (1H, m), 2.03 (2H, m), 1.85 (4H, m), 1.65 (2H, m).

[1264] Primer pripreme 183: 2-ciklopropilmetoksi-6-(3,4,5-trifluoro-fenil)-piridin[1264] Preparation Example 183: 2-cyclopropylmethoxy-6-(3,4,5-trifluoro-phenyl)-pyridine

[1265] 4,4,5,5-tetrametil-2-(3,4,5-trifluoro-fenil)-[1,3,2]dioksaborolan (0.04 g, 0.15 mmol) dobijen u primeru pripreme 165, 2-bromo-6-(ciklopropilmetoksi)-piridin (0.035 g, 0.15 mmol) dobijen u primeru pripreme 232, 2M Na<2>CO<3>vodeni rastvor (0.2 mL) i Pd(PPh<3>)<4>(0.01 g, 0.01 mmol) su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.034 g, 80%).[1265] 4,4,5,5-tetramethyl-2-(3,4,5-trifluoro-phenyl)-[1,3,2]dioxaborolane (0.04 g, 0.15 mmol) obtained in preparation example 165, 2-bromo-6-(cyclopropylmethoxy)-pyridine (0.035 g, 0.15 mmol) obtained in preparation example 232, 2M Na<2>CO<3>aqueous solution (0.2 mL) and Pd(PPh<3>)<4> (0.01 g, 0.01 mmol) were reacted in the same manner as in Preparation Example 13 to give the title compound (0.034 g, 80%).

[1266] <1>H-NMR (CDCl<3>) δ 7.64 (3H, m), 7.24 (1H, d), 6.74 (1H, d), 4.23 (2H, d), 1.33 (1H, m), 0.64 (2H, m), 0.39 (2H, m).[1266] <1>H-NMR (CDCl<3>) δ 7.64 (3H, m), 7.24 (1H, d), 6.74 (1H, d), 4.23 (2H, d), 1.33 (1H, m), 0.64 (2H, m), 0.39 (2H, m).

[1268] Primer pripreme 184: 2-ciklobutilsulfanil-6-(3,4,5-trifluoro-fenil)-piridin[1268] Preparation Example 184: 2-cyclobutylsulfanyl-6-(3,4,5-trifluoro-phenyl)-pyridine

[1269] 4,4,5,5-tetrametil-2-(3,4,5-trifluoro-fenil)-[1,3,2]dioksaborolan (0.050 g, 0.19 mmol) dobijen u primeru pripreme 165, 2-bromo-6-ciklobutilsulfanil-piridin (0.047 g, 0.19 mmol) dobijen u primeru pripreme 233, 2M Na<2>CO<3>vodeni rastvor (0.3 mL) i Pd(PPh<3>)<4>(0.011 g, 0.01 mmol) su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.03 g, 52%).[1269] 4,4,5,5-tetramethyl-2-(3,4,5-trifluoro-phenyl)-[1,3,2]dioxaborolane (0.050 g, 0.19 mmol) obtained in preparation example 165, 2-bromo-6-cyclobutylsulfanyl-pyridine (0.047 g, 0.19 mmol) obtained in preparation example 233, 2M Na<2>CO<3>aqueous solution (0.3 mL) and Pd(PPh<3>)<4> (0.011 g, 0.01 mmol) were reacted in the same manner as in Preparation Example 13 to give the title compound (0.03 g, 52%).

[1270] <1>H-NMR (CDCl<3>) δ 7.66 (2H, m), 7.53 (1H, t), 7.29 (1H, d), 7.06 (1H, d), 4.41 (1H, m), 2.60 (2H, m), 2.20-2.10 (4H, m).[1270] <1>H-NMR (CDCl<3>) δ 7.66 (2H, m), 7.53 (1H, t), 7.29 (1H, d), 7.06 (1H, d), 4.41 (1H, m), 2.60 (2H, m), 2.20-2.10 (4H, m).

[1272] Primer pripreme 185: 2-ciklopentilsulfanil-6-(3,4,5-trifluoro-fenil)-piridin[1272] Preparation Example 185: 2-cyclopentylsulfanyl-6-(3,4,5-trifluoro-phenyl)-pyridine

[1273] 4,4,5,5-tetrametil-2-(3,4,5-trifluoro-fenil)-[1,3,2]dioksaborolan (0.050 g, 0.19 mmol) dobijen u primeru pripreme 165, 2-bromo-6-ciklopentilsulfanil-piridin (0.050 g, 0.19 mmol) dobijen u primeru pripreme 234, 2M Na<2>CO<3>vodeni rastvor (0.3 mL) i Pd(PPh<3>)<4>(0.011 g, 0.01 mmol) su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.042 g, 71%).[1273] 4,4,5,5-tetramethyl-2-(3,4,5-trifluoro-phenyl)-[1,3,2]dioxaborolane (0.050 g, 0.19 mmol) obtained in preparation example 165, 2-bromo-6-cyclopentylsulfanyl-pyridine (0.050 g, 0.19 mmol) obtained in preparation example 234, 2M Na<2>CO<3>aqueous solution (0.3 mL) and Pd(PPh<3>)<4> (0.011 g, 0.01 mmol) were reacted in the same manner as in Preparation Example 13 to give the title compound (0.042 g, 71%).

[1274] <1>H-NMR (CDCl<3>) δ 7.66 (2H, m), 7.52 (1H, t), 7.27 (1H, d), 7.11 (1H, d), 4.13 (1H, m), 2.22 (2H, m), 1.80-1.63 (6H, m).[1274] <1>H-NMR (CDCl<3>) δ 7.66 (2H, m), 7.52 (1H, t), 7.27 (1H, d), 7.11 (1H, d), 4.13 (1H, m), 2.22 (2H, m), 1.80-1.63 (6H, m).

[1276] Primer pripreme 186: etil estar 4-(2'-hidroksi-5'-metil-bifenil-4-ilsulfanil)-buterne kiseline[1276] Preparation Example 186: 4-(2'-hydroxy-5'-methyl-biphenyl-4-ylsulfanyl)-butyric acid ethyl ester

[1277] Etil estar 4-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.1 g, 0.28 mmol) dobijen u primeru pripreme 159 i 2-bromo-4-metil-fenol (0.038 ml, 0.31 mmol) su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.02 g, 21%).[1277] 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.1 g, 0.28 mmol) obtained in Preparation Example 159 and 2-bromo-4-methyl-phenol (0.038 ml, 0.31 mmol) were reacted in the same manner as in Preparation Example 13 to give title compound (0.02 g, 21%).

[1278] <1>H-NMR (CDCl<3>) δ 7.47 (2H, d), 7.39 (2H, d), 7.02 (2H, m), 6.86 (1H, d), 5.00 (1H, s), 4.12 (2H, q), 3.00 (2H, t), 2.47 (2H, t), 2.30 (3H, s), 1.99 (2H, m), 1.25 (3H, t).[1278] <1>H-NMR (CDCl<3>) δ 7.47 (2H, d), 7.39 (2H, d), 7.02 (2H, m), 6.86 (1H, d), 5.00 (1H, s), 4.12 (2H, q), 3.00 (2H, t), 2.47 (2H, t), 2.30 (3H, s), 1.99 (2H, m), 1.25 (3H, t).

[1280] Primer pripreme 187: etil estar 4-(2'-ciklopentiloksi-5'-metil-bifenil-4-ilsulfanil)-buterne kiseline [0503] Etil estar 4-(2'-hidroksi-5'-metil-bifenil-4-ilsulfanil)-buterne kiseline (0.02 g, 0.06 mmol) dobijen u primeru pripreme 186, bromo-ciklopentan (0.01 mL) i Cs<2>CO<3>(0.06 g, 0.18 mmol) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.02 g, 83%).[1280] Preparation example 187: 4-(2'-cyclopentyloxy-5'-methyl-biphenyl-4-ylsulfanyl)-butyric acid ethyl ester [0503] 4-(2'-hydroxy-5'-methyl-biphenyl-4-ylsulfanyl)-butyric acid ethyl ester (0.02 g, 0.06 mmol) obtained in preparation example 186, bromo-cyclopentane (0.01 mL) and Cs<2>CO<3> (0.06 g, 0.18 mmol) were reacted in the same manner as in Step B of Preparation Example 44 to give the title compound (0.02 g, 83%).

[1281] <1>H-NMR (CDCl<3>) δ 7.45 (2H, d), 7.32 (2H, d), 7.10 (1H, s), 7.04 (1H, m), 6.85 (1H, d), 4.67 (1H, m), 4.12 (2H, q), 3.00 (2H, t), 2.48 (2H, t), 2.31 (3H, s), 1.98 (2H, m), 1.78 (4H, m), 1.64-1.53 (4H, m), 1.25 (3H, t).[1281] <1>H-NMR (CDCl<3>) δ 7.45 (2H, d), 7.32 (2H, d), 7.10 (1H, s), 7.04 (1H, m), 6.85 (1H, d), 4.67 (1H, m), 4.12 (2H, q), 3.00 (2H, t), 2.48 (2H, t), 2.31 (3H, s), 1.98 (2H, m), 1.78 (4H, m), 1.64-1.53 (4H, m), 1.25 (3H, t).

[1283] Primer pripreme 188: metil estar 2-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-propionske kiseline[1283] Preparation Example 188: 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-propionic acid methyl ester

[1284] Faza A: metil estar 2-(4-bromo-fenilsulfanil)-propionske kiseline[1284] Phase A: 2-(4-bromo-phenylsulfanyl)-propionic acid methyl ester

[1285] 4-bromo-benzentiol (0.5 g, 2.64 mmol), NaH (60% u mineralnom ulju, 0.11 g, 2.64 mmol) i metil 2-bromopropionat (0.32 mL, 2.91 mmol) su izreagovani na isti način kao u primeru pripreme 12 da bi se dobilo naslovno jedinjenje (0.58 g, 80 %).[1285] 4-Bromo-benzenethiol (0.5 g, 2.64 mmol), NaH (60% in mineral oil, 0.11 g, 2.64 mmol) and methyl 2-bromopropionate (0.32 mL, 2.91 mmol) were reacted in the same manner as in Preparation Example 12 to give the title compound (0.58 g, 80%).

[1286] <1>H-NMR (CDCl<3>) δ 7.43 (2H, d), 7.30 (2H, d), 3.76 (1H, q), 3.66 (3H, s), 1.47 (3H, d).[1286] <1>H-NMR (CDCl<3>) δ 7.43 (2H, d), 7.30 (2H, d), 3.76 (1H, q), 3.66 (3H, s), 1.47 (3H, d).

[1288] Faza B: metil estar 2-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-propionske kiseline [0507] Metil estar 2-(4-bromo-fenilsulfanil)-propionske kiseline (0.62 g, 2.2 mmol) dobijen u fazi A, bis(pinakolato)dibor (0.63 g, 2.4 mmol), kalijumacetat (0.55 g, 5.6 mmol) i dihloro[1,1'-bis(difenilfosfino)ferocen]paladijum(II) (0.16 g, 0.22 mmol) su izreagovani na isti način kao u fazi A primera pripreme 1 da bi se dobilo naslovno jedinjenje (0.30 g, 42%).[1288] Phase B: 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-propionic acid methyl ester [0507] 2-(4-bromo-phenylsulfanyl)-propionic acid methyl ester (0.62 g, 2.2 mmol) obtained in phase A, bis(pinacolato)diboron (0.63 g, 2.4 mmol). potassium acetate (0.55 g, 5.6 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (0.16 g, 0.22 mmol) were reacted in the same manner as in Step A of Preparation Example 1 to give the title compound (0.30 g, 42%).

[1289] <1>H-NMR (CDCl<3>) δ 7.72 (2H, d), 7.40 (2H, d), 3.88 (1H, q), 3.67 (3H, s), 1.51 (3H, d), 1.33 (12H, s).[1289] <1>H-NMR (CDCl<3>) δ 7.72 (2H, d), 7.40 (2H, d), 3.88 (1H, q), 3.67 (3H, s), 1.51 (3H, d), 1.33 (12H, s).

[1291] Primer pripreme 189: metil estar 2-[4-(2-ciklopentiloksi-piridin-3-il)-fenilsulfanil]-propionske kiseline [0509] Metil estar 2-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-propionske kiseline (0.15 g, 0.46 mmol) dobijen u primeru pripreme 188 i 2-ciklopentoksi-3-jodo-piridin (0.16 g, 0.56 mmol) dobijen u primeru pripreme 38 su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.045 g, 27%).[1291] Preparation example 189: 2-[4-(2-cyclopentyloxy-pyridin-3-yl)-phenylsulfanyl]-propionic acid methyl ester [0509] 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-propionic acid methyl ester (0.15 g, 0.46 mmol) obtained in preparation example 188 and 2-cyclopentoxy-3-iodo-pyridine (0.16 g, 0.56 mmol) obtained in Preparative Example 38 were reacted in the same manner as in Preparative Example 13 to give the title compound (0.045 g, 27%).

[1292] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.59 (1H, m), 7.50 (2H, d), 7.46 (2H, d), 6.91 (1H, m), 5.50 (1H, m), 3.88 (1H, m), 3.68 (3H, s), 1.93 (2H, m), 1.82-1.58 (6H, m), 1.53 (3H, d)[1292] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.59 (1H, m), 7.50 (2H, d), 7.46 (2H, d), 6.91 (1H, m), 5.50 (1H, m), 3.88 (1H, m), 3.68 (3H, s), 1.93 (2H, m), 1.82-1.58 (6H, m), 1.53 (3H, d)

[1294] Primer pripreme 190: etil estar (E)-4-[4-(2-ciklopentiloksi-piridin-3-il)-fenilsulfanil]-pent-2-pelargonske kiseline[1294] Preparation example 190: (E)-4-[4-(2-cyclopentyloxy-pyridin-3-yl)-phenylsulfanyl]-pent-2-pelargonic acid ethyl ester

[1295] Nakon što je metil estar 2-[4-(2-ciklopentiloksi-piridin-3-il)-fenilsulfanil]-propionske kiseline (0.07 g, 0.19 mmol) dobijen u primeru pripreme 189 rastvoren u DCM-u (1 mL), dodat je DIBAL-H (1.5M toluen, 0.15 mL, 0.21 mol) na -78°C. Zatim je dodat rastvor pripremljen rastvaranjem NaH (60% u mineralnom ulju, 0.009 g, 0.23 mmol) i trietilfosfonoacetata (0.053 g, 0.23 mmol) u DCM-u (1 mL) uz mešanje od 30 minuta, i mešavina je mešana na sobnoj temperaturi 18 sati. Reaktant je dodat sa vodenim rastvorom kalijum natrijum tartrata a zatim je ekstrahovan DCM-om. Organski sloj je izdvojen i osušen sa MgSO<4>, i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.023 g, 29 %).[1295] After 2-[4-(2-cyclopentyloxy-pyridin-3-yl)-phenylsulfanyl]-propionic acid methyl ester (0.07 g, 0.19 mmol) obtained in Preparative Example 189 was dissolved in DCM (1 mL), DIBAL-H (1.5 M toluene, 0.15 mL, 0.21 mol) was added at -78°C. A solution prepared by dissolving NaH (60% in mineral oil, 0.009 g, 0.23 mmol) and triethylphosphonoacetate (0.053 g, 0.23 mmol) in DCM (1 mL) was then added with stirring for 30 min, and the mixture was stirred at room temperature for 18 h. The reactant was added with aqueous potassium sodium tartrate and then extracted with DCM. The organic layer was separated and dried with MgSO<4> , and purified by column chromatography to give the title compound (0.023 g, 29 %).

[1296] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.59 (1H, m), 7.49 (2H, d), 7.40 (2H, d), 6.90 (2H, m), 5.64 (1H, d), 5.50 (1H, m), 4.16 (2H, m), 3.85 (1H, m), 1.93 (2H, m), 1.82-1.58 (6H, m), 1.46 (3H, d), 1.24 (3H, t).[1296] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.59 (1H, m), 7.49 (2H, d), 7.40 (2H, d), 6.90 (2H, m), 5.64 (1H, d), 5.50 (1H, m), 4.16 (2H, m), 3.85 (1H, m), 1.93 (2H, m), 1.82-1.58 (6H, m), 1.46 (3H, d), 1.24 (3H, t).

[1298] Primer pripreme 191: etil estar 4-[4-(2-ciklopentiloksi-piridin-3-il)-fenilsulfanil]-valerijanske kiseline [0513] Nakon što je etil estar (E)-4-[4-(2-ciklopentiloksi-piridin-3-il)-fenilsulfanil]-pent-2-pelargonske kiseline (0.023 g, 0.06 mmol) dobijen u primeru pripreme 190 rastvoren u etanolu (0.8 mL) i THF-u (0.3 mL), dodat je kobalt(II) hlorid 6 hidrat(0.016 g, 0.07 mmol). Zatim je dodat NaBH<4>(0.005 g, 0.14 mol) na 0 °C, mešavina je mešana 4 sata na sobnoj temperaturi. Reaktantu je dodata voda a zatim je ekstrahovan sa Et<2>O. Organski sloj je izdvojen i osušen sa MgSO<4>, i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.01 g, 43 %).[1298] Preparation example 191: 4-[4-(2-cyclopentyloxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid ethyl ester [0513] After (E)-4-[4-(2-cyclopentyloxy-pyridin-3-yl)-phenylsulfanyl]-pent-2-pelargonic acid ethyl ester (0.023 g, 0.06 mmol) was obtained in preparation example 190 dissolved in ethanol (0.8 mL) and THF (0.3 mL), cobalt(II) chloride 6 hydrate (0.016 g, 0.07 mmol) was added. Then NaBH<4> (0.005 g, 0.14 mol) was added at 0 °C, the mixture was stirred for 4 hours at room temperature. Water was added to the reactant and then extracted with Et<2>O. The organic layer was separated and dried with MgSO<4> , and purified by column chromatography to give the title compound (0.01 g, 43 %).

[1299] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.59 (1H, m), 7.49 (2H, d), 7.40 (2H, d), 6.91 (1H, m), 5.51 (1H, m), 4.14 (2H, q), 3.30 (1H, m), 2.53 (2H, m), 1.93 (4H, m), 1.81-1.60 (6H, m), 1.35 (3H, d), 1.24 (3H, t).[1299] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.59 (1H, m), 7.49 (2H, d), 7.40 (2H, d), 6.91 (1H, m), 5.51 (1H, m), 4.14 (2H, q), 3.30 (1H, m), 2.53 (2H, m), 1.93 (4H, m), 1.81-1.60 (6H, m), 1.35 (3H, d), 1.24 (3H, t).

[1301] Primer pripreme 192: metil estar 2-[4-(2-izopropoksi-piridin-3-il)-fenil sulfanil]-propionske kiseline [0515] Metil estar 2-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-propionske kiseline (0.15 g, 0.46 mmol) dobijen u primeru pripreme 188 i 3-jodo-2-izopropoksi-piridin (0.15 g, 0.56 mmol) dobijen u primeru pripreme 37 su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.043 g, 27%).[1301] Preparation example 192: 2-[4-(2-isopropoxy-pyridin-3-yl)-phenyl sulfanyl]-propionic acid methyl ester [0515] 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-propionic acid methyl ester (0.15 g, 0.46 mmol) obtained in preparation example 188 and 3-Iodo-2-isopropoxy-pyridine (0.15 g, 0.56 mmol) obtained in Preparative Example 37 was reacted in the same manner as in Preparative Example 13 to give the title compound (0.043 g, 27%).

[1302] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.57 (1H, m), 7.53 (2H, d), 7.47 (2H, d), 6.91 (1H, m), 5.39 (1H, m), 3.83 (1H, m), 3.69 (3H, s), 1.55 (3H, d), 1.33 (6H, d)[1302] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.57 (1H, m), 7.53 (2H, d), 7.47 (2H, d), 6.91 (1H, m), 5.39 (1H, m), 3.83 (1H, m), 3.69 (3H, s), 1.55 (3H, d), 1.33 (6H, d)

[1304] Primer pripreme 193: etil estar (E)-4-[4-(2-izopropoksi-piridin-3-il)-fenil sulfanil]-pent-2-pelargonske kiseline[1304] Preparation example 193: (E)-4-[4-(2-isopropoxy-pyridin-3-yl)-phenyl sulfanyl]-pent-2-pelargonic acid ethyl ester

[1305] Metil estar 2-[4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-propionske kiseline (0.054 g, 0.16 mmol) dobijen u primeru pripreme 192, DIBAL-H (1.5M toluen, 0.12 mL, 0.18 mol), NaH (60% u mineralnom ulju, 0.008 g, 0.19 mmol) i trietilfosfonoacetat (0.044 g, 0.19 mmol) su izreagovani na isti način kao u primeru pripreme 190 da bi se dobilo naslovno jedinjenje (0.025 g, 41 %).[1305] 2-[4-(2-Isopropoxy-pyridin-3-yl)-phenylsulfanyl]-propionic acid methyl ester (0.054 g, 0.16 mmol) obtained in Preparation Example 192, DIBAL-H (1.5M toluene, 0.12 mL, 0.18 mol), NaH (60% in mineral oil, 0.008 g, 0.19 mmol) and triethylphosphonoacetate (0.044 g, 0.19 mmol) were reacted in the same manner as in Preparation Example 190 to give the title compound (0.025 g, 41 %).

[1306] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.59 (1H, m), 7.52 (2H, d), 7.42 (2H, d), 6.92 (2H, m), 5.67 (1H, d), 5.39 (1H, m), 4.18 (2H, q), 3.85 (1H, m), 1.46 (3H, d), 1.34 (6H, d), 1.25 (3H, t).[1306] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.59 (1H, m), 7.52 (2H, d), 7.42 (2H, d), 6.92 (2H, m), 5.67 (1H, d), 5.39 (1H, m), 4.18 (2H, q), 3.85 (1H, m), 1.46 (3H, d), 1.34 (6H, d), 1.25 (3H, t).

[1308] Primer pripreme 194: metil estar 2-(4-bromo-2,6-difluoro-fenilsulfanil)-propionske kiseline [0519] 4-bromo-2,6-difluoro-benzentiol (0.45 g, 2.0 mmol) dobijen u primeru pripreme 168, NaH (60% u mineralnom ulju, 0.08 g, 2.0 mmol) i metil 2-bromopropionat (0.24 mL, 2.2 mmol) su izreagovani na isti način kao u primeru pripreme 12 da bi se dobilo naslovno jedinjenje (0.52 g, 83 %).[1308] Preparation example 194: 2-(4-bromo-2,6-difluoro-phenylsulfanyl)-propionic acid methyl ester [0519] 4-bromo-2,6-difluoro-benzenethiol (0.45 g, 2.0 mmol) obtained in preparation example 168, NaH (60% in mineral oil, 0.08 g, 2.0 mmol) and methyl 2-bromopropionate. (0.24 mL, 2.2 mmol) were reacted in the same manner as in Preparation Example 12 to give the title compound (0.52 g, 83 %).

[1309] <1>H-NMR (CDCl<3>) δ 7.14 (2H, d), 3.72 (1H, q), 3.69 (3H, s), 1.45 (3H, d).[1309] <1>H-NMR (CDCl<3>) δ 7.14 (2H, d), 3.72 (1H, q), 3.69 (3H, s), 1.45 (3H, d).

[1311] Primer pripreme 195: metil estar 2-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-propionske kiseline[1311] Preparation Example 195: 2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-propionic acid methyl ester

[1312] Metil estar 2-(4-bromo-2,6-difluoro-fenilsulfanil)-propionske kiseline (0.52 g, 1.67 mmol) dobijen u primeru pripreme 194, bis(pinakolato)dibor (0.47 g, 1.84 mmol), kalijumacetat (0.41 g, 4.18 mmol) i dihloro[1,1'-bis(difenilfosfino)ferocen]paladijum(II) (0.12 g, 0.17 mmol) su izreagovani na isti način kao u fazi A primera pripreme 1 da bi se dobilo naslovno jedinjenje (0.27 g, 45%).[1312] 2-(4-Bromo-2,6-difluoro-phenylsulfanyl)-propionic acid methyl ester (0.52 g, 1.67 mmol) obtained in Preparation Example 194, bis(pinacolato)diboron (0.47 g, 1.84 mmol), potassium acetate (0.41 g, 4.18 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (0.12 g, 0.17 mmol) were reacted in the same manner as in Step A of Preparation Example 1 to give the title compound (0.27 g, 45%).

[1313] <1>H-NMR (CDCl<3>) δ 7.32 (2H, d), 3.80 (1H, q), 3.64 (3H, s), 1.46 (3H, d), 1.33 (12H, s).[1313] <1>H-NMR (CDCl<3>) δ 7.32 (2H, d), 3.80 (1H, q), 3.64 (3H, s), 1.46 (3H, d), 1.33 (12H, s).

[1315] Primer pripreme 196: metil estar 2-[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-propionske kiseline[1315] Preparation Example 196: 2-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-propionic acid methyl ester

[1316] Metil estar 2-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-propionske kiseline (0.1 g, 0.28 mmol) dobijen u primeru pripreme 195 i 2-ciklopentoksi-3-jodo-piridin (0.12 g, 0.42 mmol) dobijen u primeru pripreme 38 su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.052 g, 47%).[1316] 2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-propionic acid methyl ester (0.1 g, 0.28 mmol) obtained in Preparation Example 195 and 2-cyclopentoxy-3-iodo-pyridine (0.12 g, 0.42 mmol) obtained in Preparation Example 38 were reacted in the same manner as in Preparation Example 13 to give the title compound (0.052 g, 47%).

[1317] <1>H-NMR (CDCl<3>) δ 8.18 (1H, m), 7.62 (1H, m), 7.22 (2H, d), 6.95 (1H, m), 5.54 (1H, m), 3.80 (1H, m), 3.66 (3H, s), 1.95 (2H, m), 1.82-1.63 (6H, m), 1.48 (3H, d).[1317] <1>H-NMR (CDCl<3>) δ 8.18 (1H, m), 7.62 (1H, m), 7.22 (2H, d), 6.95 (1H, m), 5.54 (1H, m), 3.80 (1H, m), 3.66 (3H, s), 1.95 (2H, m), 1.82-1.63 (6H, m), 1.48 (3H, d).

[1319] Primer pripreme 197: etil estar (E)-4-[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-pent-2-pelargonske kiseline[1319] Preparation Example 197: (E)-4-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-pent-2-pelargonic acid ethyl ester

[1320] Metil estar 2-[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-propionske kiseline (0.052 g, 0.13 mmol) dobijen u primeru pripreme 196, DIBAL-H (1.5M toluene, 0.10 mL, 0.14 mol), NaH (60% u mineralnom ulju, 0.006 g, 0.16 mmmol) i trietil fosfonoacetat (0.035 g, 0.16 mmol) su izreagovani na isti način kao u primeru pripreme 190 da bi se dobilo naslovno jedinjenje (0.041 g, 71 %).[1320] 2-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-propionic acid methyl ester (0.052 g, 0.13 mmol) obtained in Preparative Example 196, DIBAL-H (1.5M toluene, 0.10 mL, 0.14 mol), NaH (60% in mineral oil, 0.006 g, 0.16 mmol) and triethyl phosphonoacetate (0.035 g, 0.16 mmol) were reacted in the same manner as in Preparation Example 190 to give the title compound (0.041 g, 71 %).

[1321] <1>H-NMR (CDCl<3>) δ 8.18 (1H, m), 7.61 (1H, m), 7.19 (2H, d), 6.95 (1H, m), 6.85 (1H, m), 5.60 (1H, d), 5.52 (1H, m), 4.14 (2H, m), 3.95 (1H, m), 1.95 (2H, m), 1.81-1.64 (6H, m), 1.48 (3H, d), 1.24 (3H, t).[1321] <1>H-NMR (CDCl<3>) δ 8.18 (1H, m), 7.61 (1H, m), 7.19 (2H, d), 6.95 (1H, m), 6.85 (1H, m), 5.60 (1H, d), 5.52 (1H, m), 4.14 (2H, m), 3.95 (1H, m), 1.95 (2H, m), 1.81-1.64 (6H, m), 1.48 (3H, d), 1.24 (3H, t).

[1323] Primer pripreme 198: metil estar 2-[4-(2-ciklopentilsulfanil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-propionske kiseline[1323] Preparation Example 198: 2-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-propionic acid methyl ester

[1324] Metil estar 2-[2,6-difluoro-4-(4,4,5 ,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-propionske kiseline (0.1 g, 0.28 mmol) dobijen u primeru pripreme 195 i 2-ciklopentilsulfanil-3-jodopiridin (0.13 g, 0.42 mmol) dobijen u primeru pripreme 39 su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.064 g, 56%).[1324] 2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-propionic acid methyl ester (0.1 g, 0.28 mmol) obtained in preparation example 195 and 2-cyclopentylsulfanyl-3-iodopyridine (0.13 g, 0.42 mmol) obtained in preparation example 39 were reacted in the same manner as in Preparation Example 13 to give the title compound (0.064 g, 56%).

[1325] <1>H-NMR (CDCl<3>) δ 8.46 (1H, m), 7.36 (1H, m), 7.07 (3H, m), 4.10 (1H, m), 3.83 (1H, m), 3.69 (3H, s), 2.19 (2H, m), 1.72-1.55 (6H, m), 1.54 (3H, d).[1325] <1>H-NMR (CDCl<3>) δ 8.46 (1H, m), 7.36 (1H, m), 7.07 (3H, m), 4.10 (1H, m), 3.83 (1H, m), 3.69 (3H, s), 2.19 (2H, m), 1.72-1.55 (6H, m), 1.54 (3H, d).

[1327] Primer pripreme 199: etil estar (E)-4-[4-(2-ciklopentilsulfanil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-pent-2-pelargonske kiseline[1327] Preparation Example 199: (E)-4-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-pent-2-pelargonic acid ethyl ester

[1328] Metil estar 2-[4-(2-ciklopentilsulfanil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-propionske kiseline (0.064 g, 0.15 mmol) dobijen u primeru pripreme 196, DIBAL-H (1.5M toluenu, 0.11 ml, 0.17 mol), NaH (60% u mineralnom ulju, 0.008 g, 0.19 mmol) i trietilfosfonoacetat (0.042 g, 0.19 mmol) su izreagovani na isti način kao u primeru pripreme 190 da bi se dobilo naslovno jedinjenje (0.039 g, 55 %).[1328] 2-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-propionic acid methyl ester (0.064 g, 0.15 mmol) obtained in Preparation Example 196, DIBAL-H (1.5M toluene, 0.11 ml, 0.17 mol), NaH (60% in mineral oil, 0.008 g, 0.19 mmol) and triethylphosphonoacetate (0.042 g, 0.19 mmol) were reacted in the same manner as in Preparation Example 190 to give the title compound (0.039 g, 55 %).

[1329] <1>H-NMR (CDCl<3>) δ 8.45 (1H, m), 7.33 (1H, m), 7.04 (3H, m), 6.81 (1H, m), 5.60 (1H, d), 4.15 (3H, m), 3.95 (1H, m), 2.19 (2H, m), 1.72-1.51 (6H, m), 1.47 (3H, d), 1.25 (3H, t).[1329] <1>H-NMR (CDCl<3>) δ 8.45 (1H, m), 7.33 (1H, m), 7.04 (3H, m), 6.81 (1H, m), 5.60 (1H, d), 4.15 (3H, m), 3.95 (1H, m), 2.19 (2H, m), 1.72-1.51 (6H, m), 1.47 (3H, d), 1.25 (3H, t).

[1331] Primer pripreme 200: 2-ciklobutoksi-3-jodo-piridin[1331] Preparation Example 200: 2-cyclobutoxy-3-iodo-pyridine

[1332] Ciklobutanol (0.064 g, 1.34 mmol) i 2-fluoro-3-jodo-piridin (0.2 g, 0.89 mmol) su izreagovani na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (0.16 g, 66%).[1332] Cyclobutanol (0.064 g, 1.34 mmol) and 2-fluoro-3-iodo-pyridine (0.2 g, 0.89 mmol) were reacted in the same manner as in Preparation Example 37 to give the title compound (0.16 g, 66%).

[1333] <1>H-NMR (CDCl<3>) δ 8.07(1H, m), 8.00(1H, m), 6.61(1H, m), 5.18(1H, m), 2.47 (2H, m), 2.20(2H, m), 1.84(1H, m), 1.67(1H, m)[1333] <1>H-NMR (CDCl<3>) δ 8.07(1H, m), 8.00(1H, m), 6.61(1H, m), 5.18(1H, m), 2.47 (2H, m), 2.20(2H, m), 1.84(1H, m), 1.67(1H, m)

[1335] Primer pripreme 201: 2-bromo-6-izopropilsulfanil-piridin[1335] Preparation Example 201: 2-bromo-6-isopropylsulfanyl-pyridine

[1336] Nakon što su 2,6-dibromopiridin (0.2 g, 0.84 mmol) i Cs<2>CO<3>(0.41 g, 1.27 mmol) rastvoreni u DMF-u (4 mL), dodat je propan-2-tiol (0.08 mL, 0.84 mmol), i mešavina je mešana 8 sati na sobnoj temperaturi. Reaktantu je dodata voda a zatim je ekstrahovan sa EtOAc. Organski sloj je izdvojen i osušen sa MgSO<4>, i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.17 g, 89 %).[1336] After 2,6-dibromopyridine (0.2 g, 0.84 mmol) and Cs<2>CO<3> (0.41 g, 1.27 mmol) were dissolved in DMF (4 mL), propane-2-thiol (0.08 mL, 0.84 mmol) was added, and the mixture was stirred for 8 hours at room temperature. Water was added to the reactant and then extracted with EtOAc. The organic layer was separated and dried with MgSO<4> , and purified by column chromatography to give the title compound (0.17 g, 89 %).

[1337] 1H NMR (CDCl<3>) δ 7.28 (1H, t), 7.11 (1H, d), 7.08 (1H, d), 3.98 (1H, m), 1.41 (6H, d).[1337] 1H NMR (CDCl<3>) δ 7.28 (1H, t), 7.11 (1H, d), 7.08 (1H, d), 3.98 (1H, m), 1.41 (6H, d).

[1339] Primer pripreme 202: 3-jodo-2-propoksi-piridin[1339] Preparation Example 202: 3-iodo-2-propoxy-pyridine

[1340] Propanol (0.1 mL, 1.34 mmol) i 2-fluoro-3-jodo-piridin (0.2 g, 0.89 mmol) su izreagovani na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (0.11 g, 46%).[1340] Propanol (0.1 mL, 1.34 mmol) and 2-fluoro-3-iodo-pyridine (0.2 g, 0.89 mmol) were reacted in the same manner as in Preparation Example 37 to give the title compound (0.11 g, 46%).

[1341] <1>H-NMR (CDCl<3>) δ 8.08(1H, m), 8.00(1H, m), 6.61(1H, m), 4.28(2H, t), 1.82(2H, m), 1.04(3H, t)[1341] <1>H-NMR (CDCl<3>) δ 8.08(1H, m), 8.00(1H, m), 6.61(1H, m), 4.28(2H, t), 1.82(2H, m), 1.04(3H, t)

[1343] Primer pripreme 203: 3-jodo-2-propilsulfanil-piridin[1343] Preparation Example 203: 3-iodo-2-propylsulfanyl-pyridine

[1344] Nakon što su 2-fluoro-3-jodo-piridin (2.08 g, 9.3 mmol) i propan-1-tiol (0.89 mL, 9.8 mmol) dodati sa CH<3>CN (31 mL) i Cs<2>CO<3>(3.33 g, 10.2 mmol), mešavina je mešana pod refluksom 5 sati. Reaktant je ohlađen do sobne temperature i odvojen je, a ostatak je prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (1.58 g, 60%).[1344] After 2-fluoro-3-iodo-pyridine (2.08 g, 9.3 mmol) and propane-1-thiol (0.89 mL, 9.8 mmol) were added with CH<3>CN (31 mL) and Cs<2>CO<3> (3.33 g, 10.2 mmol), the mixture was stirred under reflux for 5 hours. The reactant was cooled to room temperature and separated, and the residue was purified by column chromatography to give the title compound (1.58 g, 60%).

[1345] <1>H-NMR (CDCl<3>) δ 8.40 (1H, m), 7.92 (1H, m), 6.71 (1H, m), 3.13 (2H, t), 1.75 (2H, m), 1.06 (3H, t)[1345] <1>H-NMR (CDCl<3>) δ 8.40 (1H, m), 7.92 (1H, m), 6.71 (1H, m), 3.13 (2H, t), 1.75 (2H, m), 1.06 (3H, t)

[1347] Primer pripreme 204: 3-jodo-2-pirolidin-1-il-piridin[1347] Preparation Example 204: 3-iodo-2-pyrrolidin-1-yl-pyridine

[1348] Nakon što je 2-fluoro-3-jodo-piridin (0.3 g, 1.34 mmol) rastvoren u DMF-u (5 mL), dodati su TEA (0.19 mL, 1.34 mmol) i pirolidin (0.17 mL, 2.02 mmol), i mešavina je mešana 4 sata na 60°C. Reaktantu je dodata voda a zatim je ekstrahovan sa EtOAc. Organski sloj je izdvojen i osušen sa MgSO<4>, i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.36 g, 98%).[1348] After 2-fluoro-3-iodo-pyridine (0.3 g, 1.34 mmol) was dissolved in DMF (5 mL), TEA (0.19 mL, 1.34 mmol) and pyrrolidine (0.17 mL, 2.02 mmol) were added, and the mixture was stirred at 60°C for 4 hours. Water was added to the reactant and then extracted with EtOAc. The organic layer was separated and dried with MgSO<4> , and purified by column chromatography to give the title compound (0.36 g, 98%).

[1349] 1H NMR (CDCl<3>) δ 8.11 (1H, m), 7.97 (1H, m), 6.39 (1H, m), 3.65 (4H, m), 1.92 (4H, m).[1349] 1H NMR (CDCl<3>) δ 8.11 (1H, m), 7.97 (1H, m), 6.39 (1H, m), 3.65 (4H, m), 1.92 (4H, m).

[1351] Primer pripreme 205: 3-[(3-jodo-2-piridil)oksi]-5-metil-isoksazol[1351] Preparation Example 205: 3-[(3-iodo-2-pyridyl)oxy]-5-methyl-isoxazole

[1352] 2-fluoro-3-jodo-piridin (0.3 g, 1.34 mmol) i 5-metilisoksazol-3-ol (0.147 g, 1.47 mmol) su izreagovani na isti način kao u primeru pripreme 37 na 80°C da bi se dobilo naslovno jedinjenje (0.15 g, 37%).[1352] 2-Fluoro-3-iodo-pyridine (0.3 g, 1.34 mmol) and 5-methylisoxazol-3-ol (0.147 g, 1.47 mmol) were reacted in the same manner as in Preparation Example 37 at 80°C to give the title compound (0.15 g, 37%).

[1353] <1>H-NMR (CDCl<3>) δ 8.17 (2H, m), 6.87 (1H, m), 6.03 (1H, s), 2.44 (3H, s)[1353] <1>H-NMR (CDCl<3>) δ 8.17 (2H, m), 6.87 (1H, m), 6.03 (1H, s), 2.44 (3H, s)

[1355] Primer pripreme 206: 2-[(3-jodo-2-piridil)oksi]-N,N-dimetil-etanamin[1355] Preparation Example 206: 2-[(3-iodo-2-pyridyl)oxy]-N,N-dimethyl-ethanamine

[1356] 2-fluoro-3-jodo-piridin (0.3 g, 1.34 mmol) i 2-(dimetilamino)etanol (0.131 g, 1.47 mmol) su izreagovani na isti način kao u primeru pripreme 37 na 80 °C da bi se dobilo naslovno jedinjenje (0.29 g, 75%).[1356] 2-Fluoro-3-iodo-pyridine (0.3 g, 1.34 mmol) and 2-(dimethylamino)ethanol (0.131 g, 1.47 mmol) were reacted in the same manner as in Preparative Example 37 at 80 °C to give the title compound (0.29 g, 75%).

[1357] <1>H-NMR (CDCl<3>) δ 8.09 (1H, m), 8.02 (1H, m), 6.64 (1H, m), 4.46 (2H, t), 2.79 (2H, t), 2.38 (6H, s)[1357] <1>H-NMR (CDCl<3>) δ 8.09 (1H, m), 8.02 (1H, m), 6.64 (1H, m), 4.46 (2H, t), 2.79 (2H, t), 2.38 (6H, s)

[1359] Primer pripreme 207: 2-[2-(aziridin-1-il)etoksi]-3-jodo-piridin[1359] Preparation Example 207: 2-[2-(aziridin-1-yl)ethoxy]-3-iodo-pyridine

[1360] 2-fluoro-3-jodo-piridin (0.3 g, 1.34 mmol) i2-(aziridin-1-il)etanol (0.117 g, 1.34 mmol) su izreagovani na isti način kao u primeru pripreme 37 na 80°C da bi se dobilo naslovno jedinjenje (0.19 g, 49%).[1360] 2-Fluoro-3-iodo-pyridine (0.3 g, 1.34 mmol) and 2-(aziridin-1-yl)ethanol (0.117 g, 1.34 mmol) were reacted in the same manner as in Preparation Example 37 at 80°C to give the title compound (0.19 g, 49%).

[1361] <1>H-NMR (CDCl<3>) δ 8.09 (1H, m), 8.02 (1H, m), 6.64 (1H, m), 4.52 (2H, t), 2.65 (2H, t), 1.82 (2H, m), 1.35 (2H, m)[1361] <1>H-NMR (CDCl<3>) δ 8.09 (1H, m), 8.02 (1H, m), 6.64 (1H, m), 4.52 (2H, t), 2.65 (2H, t), 1.82 (2H, m), 1.35 (2H, m)

[1363] Primer pripreme 208: 2-(furilmetoksi)-3-jodo-piridin[1363] Preparation Example 208: 2-(furylmethoxy)-3-iodo-pyridine

[1364] 2-fluoro-3-jodo-piridin (0.3 g, 1.34 mmol) i 3-furilmetanol (0.132 g, 1.34 mmol) su izreagovani na isti način kao u primeru pripreme 37 na 80°C da bi se dobilo naslovno jedinjenje (0.36 g, 89%).[1364] 2-Fluoro-3-iodo-pyridine (0.3 g, 1.34 mmol) and 3-furylmethanol (0.132 g, 1.34 mmol) were reacted in the same manner as in Preparation Example 37 at 80°C to give the title compound (0.36 g, 89%).

[1365] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 8.04 (1H, m), 7.56 (1H, s), 7.41 (1H, s), 6.65 (1H, m), 6.53 (1H, m), 5.30 (2H, s)[1365] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 8.04 (1H, m), 7.56 (1H, s), 7.41 (1H, s), 6.65 (1H, m), 6.53 (1H, m), 5.30 (2H, s)

[1366] Primer pripreme 209: 2-(2- furilmetoksi)-3-jodo-piridin[1366] Preparation Example 209: 2-(2-furylmethoxy)-3-iodo-pyridine

[1367] 2-fluoro-3-jodo-piridin (0.3 g, 1.34 mmol) i 2-furilmetanol (0.132 g, 1.34 mmol) su izreagovani na isti način kao u primeru pripreme 37 na 80°C da bi se dobilo naslovno jedinjenje (0.334 g, 83%).[1367] 2-Fluoro-3-iodo-pyridine (0.3 g, 1.34 mmol) and 2-furylmethanol (0.132 g, 1.34 mmol) were reacted in the same manner as in Preparation Example 37 at 80°C to give the title compound (0.334 g, 83%).

[1368] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 8.03 (1H, m), 7.44 (1H, m), 6.67 (1H, m), 6.47 (1H, m), 6.37 (1H, m), 5.38 (2H, s)[1368] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 8.03 (1H, m), 7.44 (1H, m), 6.67 (1H, m), 6.47 (1H, m), 6.37 (1H, m), 5.38 (2H, s)

[1370] Primer pripreme 210: 3-jodo-2-[(3-metiloksetan-3-il)metoksi] piridin[1370] Preparation Example 210: 3-iodo-2-[(3-methyloxetan-3-yl)methoxy] pyridine

[1371] 2-fluoro-3-jodo-piridin (0.3 g, 1.34 mmol) i (3-metiloksetan-3-il)metanol (0.137 g, 1.34 mmol) su izreagovani na isti način kao u primeru pripreme 37 na 80°C da bi se dobilo naslovno jedinjenje (0.30 g, 74%).[1371] 2-Fluoro-3-iodo-pyridine (0.3 g, 1.34 mmol) and (3-methyloxetan-3-yl)methanol (0.137 g, 1.34 mmol) were reacted in the same manner as in Preparation Example 37 at 80°C to give the title compound (0.30 g, 74%).

[1372] <1>H-NMR (CDCl<3>) δ 8.11 (1H, m), 8.04 (1H, m), 6.67 (1H, m), 4.68 (2H, d), 4.46 (2H, d), 4.40 (2H, s), 1.48 (3H, s)[1372] <1>H-NMR (CDCl<3>) δ 8.11 (1H, m), 8.04 (1H, m), 6.67 (1H, m), 4.68 (2H, d), 4.46 (2H, d), 4.40 (2H, s), 1.48 (3H, s)

[1374] Primer pripreme 211: 3-jodo-2-(tetrahidrofuran-3-ilmetoksi) piridin[1374] Preparation Example 211: 3-iodo-2-(tetrahydrofuran-3-ylmethoxy) pyridine

[1375] 2-fluoro-3-jodo-piridin (0.3 g, 1.34 mmol) i tetrahidrofuran-3-ilmetanol (0.137 g, 1.34 mmol) su izreagovani na isti način kao u primeru pripreme 37 na 80°C da bi se dobilo naslovno jedinjenje (0.30 g, 74%).[1375] 2-Fluoro-3-iodo-pyridine (0.3 g, 1.34 mmol) and tetrahydrofuran-3-ylmethanol (0.137 g, 1.34 mmol) were reacted in the same manner as in Preparation Example 37 at 80°C to give the title compound (0.30 g, 74%).

[1376] <1>H-NMR (CDCl<3>) δ 8.08 (1H, m), 8.02 (1H, m), 6.65 (1H, m), 4.34 (1H, m), 4.24 (1H, m), 3.94 (2H, m), 3.80 (1H, m), 3.73 (1H, m), 2.78 (1H, m), 2.11 (1H, m), 1.80 (1H, m)[1376] <1>H-NMR (CDCl<3>) δ 8.08 (1H, m), 8.02 (1H, m), 6.65 (1H, m), 4.34 (1H, m), 4.24 (1H, m), 3.94 (2H, m), 3.80 (1H, m), 3.73 (1H, m), 2.78 (1H, m), 2.11 (1H, m), 1.80 (1H, m)

[1378] Primer pripreme 212: 3-jodo-2-(tetrahidrofuran-2-ilmetoksi) piridin[1378] Preparation Example 212: 3-iodo-2-(tetrahydrofuran-2-ylmethoxy)pyridine

[1379] 2-fluoro-3-jodo-piridin (0.3 g, 1.34 mmol) i tetrahidrofuran-2-ilmetanol (0.137 g, 1.34 mmol) su izreagovani na isti način kao u primeru pripreme 37 na 80°C da bi se dobilo naslovno jedinjenje (0.31 g, 76%).[1379] 2-Fluoro-3-iodo-pyridine (0.3 g, 1.34 mmol) and tetrahydrofuran-2-ylmethanol (0.137 g, 1.34 mmol) were reacted in the same manner as in Preparation Example 37 at 80°C to give the title compound (0.31 g, 76%).

[1380] <1>H-NMR (CDCl<3>) δ 8.08 (1H, m), 8.01 (1H, m), 6.63 (1H, m), 4.34 (3H, m), 3.99 (1H, m), 3.86 (1H, m), 2.08 (2H, m), 1.92 (2H, m)[1380] <1>H-NMR (CDCl<3>) δ 8.08 (1H, m), 8.01 (1H, m), 6.63 (1H, m), 4.34 (3H, m), 3.99 (1H, m), 3.86 (1H, m), 2.08 (2H, m), 1.92 (2H, m)

[1382] Primer pripreme 213: 2-[3-(tert-butil-dimetil-silaniloksi)-ciklopentiloksi]-3-jodo-piridin[1382] Preparation Example 213: 2-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyloxy]-3-iodo-pyridine

[1383] 3-(tert-butil-dimetil-silaniloksi)-ciklopentanol(0.44 g, 2.02 mmol) i 2-fluoro-3-jodo-piridin (0.30 g, 1.35 mmol) su izreagovani na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (0.39 g, 69 %).[1383] 3-(tert-butyl-dimethyl-silanyloxy)-cyclopentanol (0.44 g, 2.02 mmol) and 2-fluoro-3-iodo-pyridine (0.30 g, 1.35 mmol) were reacted in the same manner as in Preparation Example 37 to give the title compound (0.39 g, 69%).

[1384] <1>H-NMR (CDCl<3>) δ 8.08(1H, m), 7.99(1H, m), 6.60(1H, m), 5.49(1H, m), 4.49(1H, m), 2.23(1H, m), 2.04(3H, m), 1.80(1H, m), 1.62(1H, m), 0.88(9H, s), 0.06(6H, s)[1384] <1>H-NMR (CDCl<3>) δ 8.08(1H, m), 7.99(1H, m), 6.60(1H, m), 5.49(1H, m), 4.49(1H, m), 2.23(1H, m), 2.04(3H, m), 1.80(1H, m), 1.62(1H, m), 0.88(9H, s), 0.06(6H, s)

[1386] Primer pripreme 214: metil estar 2-[4-(2-fluoro-piridin-3-il)-fenilsulfanil]-propionske kiseline [0559] Metil estar 2-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-propionske kiseline (0.52 g, 1.62 mmol) dobijen u primeru pripreme 188 i 2-fluoro-3-jodo-piridin (0.54 g, 2.43 mmol) su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.27 g, 57%).[1386] Preparation example 214: 2-[4-(2-fluoro-pyridin-3-yl)-phenylsulfanyl]-propionic acid methyl ester [0559] 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-propionic acid methyl ester (0.52 g, 1.62 mmol) obtained in preparation example 188 and 2-Fluoro-3-iodo-pyridine (0.54 g, 2.43 mmol) was reacted in the same manner as in Preparation Example 13 to give the title compound (0.27 g, 57%).

[1387] <1>H-NMR (CDCl<3>) δ 8.20 (1H, m), 7.87 (1H, m), 7.55 (4H, m), 7.30 (1H, m), 3.88 (1H, m), 3.71 (3H, s), 1.53 (3H, d).[1387] <1>H-NMR (CDCl<3>) δ 8.20 (1H, m), 7.87 (1H, m), 7.55 (4H, m), 7.30 (1H, m), 3.88 (1H, m), 3.71 (3H, s), 1.53 (3H, d).

[1389] Primer pripreme 215: etil estar (E)-4-[4-(2-fluoro-piridin-3-il)-fenilsulfanil]-pent-2-pelargonske kiseline [0561] Metil estar 2-[4-(2-fluoro-piridin-3-il)-fenilsulfanil]-propionske kiseline (0.27 g, 0.92 mmol) dobijen u primeru pripreme 214 je izreagovan na isti način kao u primeru pripreme 190 da bi se dobilo naslovno jedinjenje (0.17 g, 54%).[1389] Preparation example 215: (E)-4-[4-(2-fluoro-pyridin-3-yl)-phenylsulfanyl]-pent-2-pelargonic acid ethyl ester [0561] 2-[4-(2-fluoro-pyridin-3-yl)-phenylsulfanyl]-propionic acid methyl ester (0.27 g, 0.92 mmol) obtained in preparation example 214 was reacted in the same way as in example preparation 190 to give the title compound (0.17 g, 54%).

[1390] <1>H-NMR (CDCl<3>) δ 8.20 (1H, m), 7.85 (1H, m), 7.52 (4H, m), 7.27 (1H, m), 6.88 (1H, q), 5.65 (1H, d), 4.16 (2H, q), 3.86 (1H, m), 1.46 (3H, d), 1.25 (3H, t).[1390] <1>H-NMR (CDCl<3>) δ 8.20 (1H, m), 7.85 (1H, m), 7.52 (4H, m), 7.27 (1H, m), 6.88 (1H, q), 5.65 (1H, d), 4.16 (2H, q), 3.86 (1H, m), 1.46 (3H, d), 1.25 (3H, t).

[1392] Primer pripreme 216: etil estar 4-[4-(2-fluoro-piridin-3-il)-fenilsulfanil]-valerijanske kiseline [0563] Nakon što je etil estar (E)-4-[4-(2-fluoro-piridin-3-il)-fenilsulfanil]-pent-2-pelargonske kiseline (0.17 g, 0.5 mmol) dobijen u primeru pripreme 215 rastvoren u 1,2-dimetoksietanu (5 mL), dodat je ptoluenesulfonhidrazid (0.65 g, 3.51 mmol), i mešavina je mešana pod refluksom 5 minuta. Zatim je dodat 1.4M NaOAc vodeni rastvor (3.6 mL), i mešavina je mešana pod refluksom 18 sati. Reaktant je razblažen vodom a zatim je ekstrahovan sa DCM-om. Organski sloj je izdvojen i osušen sa MgSO<4>, i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.1 g, 59%).[1392] Preparation example 216: 4-[4-(2-fluoro-pyridin-3-yl)-phenylsulfanyl]-valeric acid ethyl ester [0563] After (E)-4-[4-(2-fluoro-pyridin-3-yl)-phenylsulfanyl]-pent-2-pelargonic acid ethyl ester (0.17 g, 0.5 mmol) obtained in preparation example 215 was dissolved in To 1,2-dimethoxyethane (5 mL), ptoluenesulfonhydrazide (0.65 g, 3.51 mmol) was added, and the mixture was stirred under reflux for 5 min. A 1.4M NaOAc aqueous solution (3.6 mL) was then added, and the mixture was stirred under reflux for 18 hours. The reactant was diluted with water and then extracted with DCM. The organic layer was separated and dried with MgSO<4> , and purified by column chromatography to give the title compound (0.1 g, 59%).

[1393] <1>H-NMR (CDCl<3>) δ 8.20 (1H, m), 7.87 (1H, m), 7.53-7.44 (4H, m), 7.28 (1H, m), 4.14 (2H, q), 3.35 (1H, m), 2.54 (2H, t), 1.94 (2H, m), 1.32 (3H, d), 1.26 (3H, t).[1393] <1>H-NMR (CDCl<3>) δ 8.20 (1H, m), 7.87 (1H, m), 7.53-7.44 (4H, m), 7.28 (1H, m), 4.14 (2H, q), 3.35 (1H, m), 2.54 (2H, t), 1.94 (2H, m), 1.32 (3H, d), 1.26 (3H, t).

[1395] Primer pripreme 217: etil estar 4- [4-(2-ciklopentilsulfanil-piridin-3-il)-fenilsulfanil] -valerijanske kiseline[1395] Preparation Example 217: 4-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-valeric acid ethyl ester

[1396] Etil estar 4-[4-(2-fluoro-piridin-3-il)-fenilsulfanil]-valerijanske kiseline (0.03 g, 0.09 mmol) dobijen u primeru pripreme 216, ciklopentil tiol (0.01 mL, 0.09 mmol) i Cs<2>CO<3>(0.044 g, 0.13mmol) su izreagovani na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.004 g, 10%).[1396] 4-[4-(2-Fluoro-pyridin-3-yl)-phenylsulfanyl]-valeric acid ethyl ester (0.03 g, 0.09 mmol) obtained in Preparation Example 216, cyclopentyl thiol (0.01 mL, 0.09 mmol) and Cs<2>CO<3> (0.044 g, 0.13 mmol) were reacted in the same manner as in Step B of Example preparation 44 to give the title compound (0.004 g, 10%).

[1397] <1>H-NMR (CDCl<3>) δ 8.40 (1H, m), 7.41 (2H, d), 7.35 (3H, m), 7.02 (1H, m), 4.13 (2H, q), 3.30 (1H, m), 2.52 (2H, m), 2.17 (2H, m), 1.92 (2H, m), 1.71-1.48 (6H, m), 1.34 (3H, d), 1.26 (3H, t).[1397] <1>H-NMR (CDCl<3>) δ 8.40 (1H, m), 7.41 (2H, d), 7.35 (3H, m), 7.02 (1H, m), 4.13 (2H, q), 3.30 (1H, m), 2.52 (2H, m), 2.17 (2H, m), 1.92 (2H, m), 1.71-1.48 (6H, m), 1.34 (3H, d), 1.26 (3H, t).

[1399] Primer pripreme 218: metil estar 2-[2,6-difluoro-4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-propionske kiseline[1399] Preparation Example 218: 2-[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-propionic acid methyl ester

[1400] Metil estar 2-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-propionske kiseline (0.07 g, 0.19 mmol) dobijen u primeru pripreme 188 i 3-jodo-2-izopropoksi-piridin (0.077 g, 0.29 mmol) dobijen u primeru pripreme 37 su izreagovani na isti način kao u primeru pripreme 13 da bi se dobilo naslovno jedinjenje (0.05 g, 71%).[1400] 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-propionic acid methyl ester (0.07 g, 0.19 mmol) obtained in preparation example 188 and 3-iodo-2-isopropoxy-pyridine (0.077 g, 0.29 mmol) obtained in preparation example 37 were reacted to the same method as in Preparation Example 13 to give the title compound (0.05 g, 71%).

[1401] <1>H-NMR (CDCl<3>) δ 8.15 (1H, m), 7.60 (1H, m), 7.21 (2H, d), 6.93 (1H, m), 5.42 (1H, m), 3.77 (1H, m), 3.67 (3H, s), 1.50 (3H, d), 1.35 (6H, d).[1401] <1>H-NMR (CDCl<3>) δ 8.15 (1H, m), 7.60 (1H, m), 7.21 (2H, d), 6.93 (1H, m), 5.42 (1H, m), 3.77 (1H, m), 3.67 (3H, s), 1.50 (3H, d), 1.35 (6H, d).

[1403] Primer pripreme 219: etil estar 4-[2,6-difluoro-4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-valerijanske kiseline[1403] Preparation example 219: 4-[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid ethyl ester

[1404] Metil estar 2-[2,6-difluoro-4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-propionske kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 218 je izreagovan na isti način kao u primeru pripreme 190 i primera pripreme 191 redom da bi se dobilo naslovno jedinjenje (0.015 g, 26%).[1404] 2-[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-propionic acid methyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 218 was reacted in the same manner as in Preparation Example 190 and Preparation Example 191 respectively to give the title compound (0.015 g, 26%).

[1405] <1>H-NMR (CDCl<3>) δ 8.21 (1H, m), 7.65 (1H, m), 7.24 (2H, d), 6.97 (1H, m), 5.46 (1H, m), 4.17 (2H, q), 3.36 (1H, m), 2.60 (2H, m), 1.93 (2H, m), 1.40 (6H, d), 1.34 (3H, d), 1.27 (3H, t).[1405] <1>H-NMR (CDCl<3>) δ 8.21 (1H, m), 7.65 (1H, m), 7.24 (2H, d), 6.97 (1H, m), 5.46 (1H, m), 4.17 (2H, q), 3.36 (1H, m), 2.60 (2H, m), 1.93 (2H, m), 1.40 (6H, d), 1.34 (3H, d), 1.27 (3H, t).

[1407] Primer pripreme 220: 3-jodo-2-(2,2,2-trifluoro-etoksi)-piridin[1407] Preparation example 220: 3-iodo-2-(2,2,2-trifluoro-ethoxy)-pyridine

[1408] 2,2,2-trifluoroetanol (0.098 mL, 1.34 mmol) i 2-fluoro-3-jodo-piridin (0.2 g, 0.89 mmol) su izreagovani na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (0.22 g, 81%).[1408] 2,2,2-trifluoroethanol (0.098 mL, 1.34 mmol) and 2-fluoro-3-iodo-pyridine (0.2 g, 0.89 mmol) were reacted in the same manner as in Preparation Example 37 to give the title compound (0.22 g, 81%).

[1409] <1>H-NMR (CDCl<3>) δ 8.08 (2H, m), 6.74 (1H, m), 4.78 (2H, m).[1409] <1>H-NMR (CDCl<3>) δ 8.08 (2H, m), 6.74 (1H, m), 4.78 (2H, m).

[1411] Primer pripreme 221: etil estar 5-(4-bromo-2,6-difluoro-fenilsulfanil)-valerijanske kiseline[1411] Preparation example 221: 5-(4-bromo-2,6-difluoro-phenylsulfanyl)-valeric acid ethyl ester

[1412] 4-bromo-2,6-difluoro-benzentiol (0.5 g, 2.22 mmol) dobijen u primeru pripreme 168, NaH (60% u mineralnom ulju, 0.1 g, 2.44 mmol) i etil 5-bromopentanoat (0.387 mL, 2.44 mmol) su izreagovani na isti način kao u primeru pripreme 12 da bi se dobilo naslovno jedinjenje (0.7 g, 89 %).[1412] 4-Bromo-2,6-difluoro-benzenethiol (0.5 g, 2.22 mmol) obtained in Preparative Example 168, NaH (60% in mineral oil, 0.1 g, 2.44 mmol) and ethyl 5-bromopentanoate (0.387 mL, 2.44 mmol) were reacted in the same manner as in Preparative Example 12 to give the title compound. (0.7 g, 89 %).

[1413] <1>H-NMR (CDCl<3>) δ 7.10 (2H, d), 4.10 (2H, q), 2.84 (2H, t), 2.27 (2H, t), 1.72 (2H, m), 1.56 (2H, m), 1.23 (3H, t).[1413] <1>H-NMR (CDCl<3>) δ 7.10 (2H, d), 4.10 (2H, q), 2.84 (2H, t), 2.27 (2H, t), 1.72 (2H, m), 1.56 (2H, m), 1.23 (3H, t).

[1415] Primer pripreme 222: etil estar 5-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-pentanoinske kiseline[1415] Preparation Example 222: 5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-pentanoic acid ethyl ester

[1416] Etil estar 5-(4-bromo-2,6-difluoro-fenilsulfanil)-valerijanske kiseline (0.7 g, 1.99 mmol) dobijen u primeru pripreme 221, bis(pinakolato)dibor (0.56 g, 2.19 mmol), kalijumacetat (0.49 g, 4.99 mmol) i dihloro[1,1'-bis(difenilfosfino)ferocen]paladijum(II) (0.15 g, 0.20 mmol) su izreagovani na isti način kao u fazi A primera pripreme 1 da bi se dobilo naslovno jedinjenje (0.42 g, 53%).[1416] 5-(4-Bromo-2,6-difluoro-phenylsulfanyl)-valeric acid ethyl ester (0.7 g, 1.99 mmol) obtained in Preparation Example 221, bis(pinacolato)diboron (0.56 g, 2.19 mmol), potassium acetate (0.49 g, 4.99 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (0.15 g, 0.20 mmol) were reacted in the same manner as in Step A of Preparation Example 1 to give the title compound (0.42 g, 53%).

[1417] <1>H-NMR (CDCl<3>) δ 7.30 (2H, d), 4.08 (2H, q), 2.90 (2H, t), 2.26 (2H, t), 1.72 (2H, m), 1.54 (2H, m), 1.32 (12H, s), 1.23 (3H, t).[1417] <1>H-NMR (CDCl<3>) δ 7.30 (2H, d), 4.08 (2H, q), 2.90 (2H, t), 2.26 (2H, t), 1.72 (2H, m), 1.54 (2H, m), 1.32 (12H, s), 1.23 (3H, t).

[1419] Primer pripreme 223: etil estar 5-(4-bromo-fenilsulfanil)-valerijanske kiseline[1419] Preparation example 223: 5-(4-bromo-phenylsulfanyl)-valeric acid ethyl ester

[1420] 4-bromo-benzentiol (0.5 g, 2.64 mmol), NaH (60% u mineralnom ulju, 0.12 g, 2.91 mmol) i etil 5-bromopentanoat (0.46 mL, 2.91 mmol) su izreagovani na isti način kao u primeru pripreme 12 da bi se dobilo naslovno jedinjenje (0.78 g, 93 %).[1420] 4-Bromo-benzenethiol (0.5 g, 2.64 mmol), NaH (60% in mineral oil, 0.12 g, 2.91 mmol) and ethyl 5-bromopentanoate (0.46 mL, 2.91 mmol) were reacted in the same manner as in Preparation Example 12 to give the title compound (0.78 g, 93%).

[1421] <1>H-NMR (CDCl<3>) δ 7.38 (2H, d), 7.16 (2H, d), 4.11 (2H, q), 2.88 (2H, t), 2.30 (2H, t), 1.75 (2H, m), 1.65 (2H, m), 1.23 (3H, t).[1421] <1>H-NMR (CDCl<3>) δ 7.38 (2H, d), 7.16 (2H, d), 4.11 (2H, q), 2.88 (2H, t), 2.30 (2H, t), 1.75 (2H, m), 1.65 (2H, m), 1.23 (3H, t).

[1423] Primer pripreme 224: etil estar 5-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-valerijanske kiseline[1423] Preparation Example 224: 5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-valeric acid ethyl ester

[1424] Etil estar 5-(4-bromo-fenilsulfanil)-valerijanske kiseline (0.78 g, 2.46 mmol) dobijen u primeru pripreme 223, bis(pinakolato)dibor (0.69 g, 2.70 mmol), kalijumacetat (0.6g, 6.15mmol) i dihloro[1,1'-bis(difenil fosfino)ferocen]paladijum(II) (0.18 g, 0.25 mmol) su izreagovani na isti način kao u fazi A primera pripreme 1 da bi se dobilo naslovno jedinjenje (0.73 g, 81%).[1424] 5-(4-bromo-phenylsulfanyl)-valeric acid ethyl ester (0.78 g, 2.46 mmol) obtained in Preparation Example 223, bis(pinacolato)diboron (0.69 g, 2.70 mmol), potassium acetate (0.6 g, 6.15 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (0.18 g, 0.25 mmol) were reacted in the same manner as in Step A of Preparation Example 1 to give the title compound (0.73 g, 81%).

[1425] <1>H-NMR (CDCl<3>) δ 7.68 (2H, d), 7.25 (2H, d), 4.10 (2H, q), 2.94 (2H, t), 2.30 (2H, t), 1.75 (2H, m), 1.68 (2H, m), 1.32 (12H, s), 1.22 (3H, t).[1425] <1>H-NMR (CDCl<3>) δ 7.68 (2H, d), 7.25 (2H, d), 4.10 (2H, q), 2.94 (2H, t), 2.30 (2H, t), 1.75 (2H, m), 1.68 (2H, m), 1.32 (12H, s), 1.22 (3H, t).

[1427] Primer pripreme 225: etil 5-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]pentanoat[1427] Preparation Example 225: Ethyl 5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pentanoate

[1428] Nakon što je 2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenol (2.23 g, 8.7mmol) dobijen u fazi B primera pripreme 2, dodati su etil 5-bromopentanoat (1.82 g, 8.7 mmol) i Cs<2>CO<3>(5.67 g, 17.4 mmol) sa CH<3>CN (29 mL), mešavina je mešana pod refluksom 2 sata. Reaktant je izdvojen i ostatak je prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (2.40 g, 72%).[1428] After 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.23 g, 8.7 mmol) was obtained in Phase B of Preparation Example 2, ethyl 5-bromopentanoate (1.82 g, 8.7 mmol) and Cs<2>CO<3> (5.67 g, 17.4 mmol) were added. with CH<3>CN (29 mL), the mixture was stirred under reflux for 2 h. The reactant was separated and the residue was purified by column chromatography to give the title compound (2.40 g, 72%).

[1429] <1>H-NMR (CDCl<3>) δ 7.30 (2H, m), 4.18 (2H, t), 4.13 (2H, q), 2.37 (2H, t), 1.81 (4H, m), 1.32 (12H, s), 1.25 (3H, t)[1429] <1>H-NMR (CDCl<3>) δ 7.30 (2H, m), 4.18 (2H, t), 4.13 (2H, q), 2.37 (2H, t), 1.81 (4H, m), 1.32 (12H, s), 1.25 (3H, t)

[1431] Primer pripreme 226: 3-jodo-2-izopropilsulfanil-piridin[1431] Preparation Example 226: 3-iodo-2-isopropylsulfanyl-pyridine

[1432] 2-fluoro-3-jodo-piridin (0.3 g, 1.34 mmol), Cs<2>CO<3>(0.66 g, 1.34 mmol) i propan-2-tiol (0.125 mL, 1.34 mmol) su izreagovani na isti način kao u primeru pripreme 201 da bi se dobilo naslovno jedinjenje (0.21 g, 56%).[1432] 2-Fluoro-3-iodo-pyridine (0.3 g, 1.34 mmol), Cs<2>CO<3> (0.66 g, 1.34 mmol) and propane-2-thiol (0.125 mL, 1.34 mmol) were reacted in the same manner as in Preparation Example 201 to give the title compound (0.21 g, 56%).

[1433] <1>H-NMR (CDCl<3>) δ 8.40 (1H, m), 7.92 (1H, m), 6.69 (1H, m), 3.95 (1H, m), 1.39 (6H, d)[1433] <1>H-NMR (CDCl<3>) δ 8.40 (1H, m), 7.92 (1H, m), 6.69 (1H, m), 3.95 (1H, m), 1.39 (6H, d)

[1435] Primer pripreme 227: 2-bromo-6-propoksi-piridin[1435] Preparation Example 227: 2-bromo-6-propoxy-pyridine

[1436] Propanol (0.07 mL, 0.92 mmol) i 2,6-dibromopiridin (0.2 g, 0.84 mmol) su izreagovani na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (0.067 g, 36%).[1436] Propanol (0.07 mL, 0.92 mmol) and 2,6-dibromopyridine (0.2 g, 0.84 mmol) were reacted in the same manner as in Preparation Example 37 to give the title compound (0.067 g, 36%).

[1437] <1>H-NMR (CDCl<3>) δ 7.39(1H, t), 7.03(1H, d), 6.65(1H, d), 4.23(2H, t), 1.76 (2H, m), 1.00(3H, t)[1437] <1>H-NMR (CDCl<3>) δ 7.39(1H, t), 7.03(1H, d), 6.65(1H, d), 4.23(2H, t), 1.76 (2H, m), 1.00(3H, t)

[1439] Primer pripreme 228: 2-bromo-6-izopropoksi-piridin[1439] Preparation Example 228: 2-bromo-6-isopropoxy-pyridine

[1440] Propan-2-ol (0.065 mL, 0.84 mmol) i 2,6-dibromopiridin (0.2 g, 0.84 mmol) su izreagovani na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (0.027 g, 14%).[1440] Propan-2-ol (0.065 mL, 0.84 mmol) and 2,6-dibromopyridine (0.2 g, 0.84 mmol) were reacted in the same manner as in Preparation Example 37 to give the title compound (0.027 g, 14%).

[1441] <1>H-NMR (CDCl<3>) δ 7.37(1H, t), 7.00(1H, d), 6.60(1H, d), 5.27(1H, m), 1.33 (6H, d)[1441] <1>H-NMR (CDCl<3>) δ 7.37(1H, t), 7.00(1H, d), 6.60(1H, d), 5.27(1H, m), 1.33 (6H, d)

[1443] Primer pripreme 229: 2-bromo-6-propilsulfanil-piridin[1443] Preparation Example 229: 2-bromo-6-propylsulfanyl-pyridine

[1444] 2,6-dibromopiridin (0.2 g, 0.84 mmol), Cs<2>CO<3>(0.412 g, 1.27 mmol) i propantiol (0.076 mL, 0.84 mmol) su izreagovani na isti način kao u primeru pripreme 201 da bi se dobilo naslovno jedinjenje (0.184 g, 93%).[1444] 2,6-Dibromopyridine (0.2 g, 0.84 mmol), Cs<2>CO<3> (0.412 g, 1.27 mmol) and propanethiol (0.076 mL, 0.84 mmol) were reacted in the same manner as in Preparation Example 201 to give the title compound (0.184 g, 93%).

[1445] <1>H-NMR (CDCl<3>) δ 7.27 (1H, t), 7.11 (2H, m), 3.13 (2H, t), 1.74 (2H, m), 1.04 (3H, t)[1445] <1>H-NMR (CDCl<3>) δ 7.27 (1H, t), 7.11 (2H, m), 3.13 (2H, t), 1.74 (2H, m), 1.04 (3H, t)

[1447] Primer pripreme 230: 2-bromo-6-(ciklobutoksi)-piridin[1447] Preparation example 230: 2-bromo-6-(cyclobutoxy)-pyridine

[1448] Ciklobutanol (0.06 mL, 0.84 mmol) i 2,6-dibromopiridin (0.2 g, 0.84 mmol) su izreagovani na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (0.06 g, 31%).[1448] Cyclobutanol (0.06 mL, 0.84 mmol) and 2,6-dibromopyridine (0.2 g, 0.84 mmol) were reacted in the same manner as in Preparation Example 37 to give the title compound (0.06 g, 31%).

[1449] <1>H-NMR (CDCl<3>) δ 7.39(1H, t), 7.01(1H, d), 6.61(1H, d), 5.14(1H, m), 2.45 (2H, m), 2.11 (2H, m), 1.82 (1H, m), 1.65(1H, m)[1449] <1>H-NMR (CDCl<3>) δ 7.39(1H, t), 7.01(1H, d), 6.61(1H, d), 5.14(1H, m), 2.45 (2H, m), 2.11 (2H, m), 1.82 (1H, m), 1.65(1H, m)

[1451] Primer pripreme 231: 2-bromo-6-(ciklopentoksi)piridin[1451] Preparation Example 231: 2-bromo-6-(cyclopentoxy)pyridine

[1452] Ciklopentanol (0.077 mL, 0.84 mmol) i 2,6-dibromopiridin (0.2 g, 0.84 mmol) su izreagovani na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (0.09 g, 44%).[1452] Cyclopentanol (0.077 mL, 0.84 mmol) and 2,6-dibromopyridine (0.2 g, 0.84 mmol) were reacted in the same manner as in Preparation Example 37 to give the title compound (0.09 g, 44%).

[1453] <1>H-NMR (CDCl<3>) δ 7.36(1H, t), 7.00(1H, d), 6.60(1H, d), 5.36 (1H, m), 1.98(2H, m), 1.77 (4H, m), 1.61(2H, m)[1453] <1>H-NMR (CDCl<3>) δ 7.36(1H, t), 7.00(1H, d), 6.60(1H, d), 5.36 (1H, m), 1.98(2H, m), 1.77 (4H, m), 1.61(2H, m)

[1455] Primer pripreme 232: 2-bromo-6-(ciklopropilmetoksi)-piridin[1455] Preparation Example 232: 2-bromo-6-(cyclopropylmethoxy)-pyridine

[1456] Ciklopropilmetanol (0.068 mL, 0.84 mmol) i 2,6-dibromopiridin (0.2 g, 0.84 mmol) su izreagovani na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (0.1 g, 53%).[1456] Cyclopropylmethanol (0.068 mL, 0.84 mmol) and 2,6-dibromopyridine (0.2 g, 0.84 mmol) were reacted in the same manner as in Preparation Example 37 to give the title compound (0.1 g, 53%).

[1457] <1>H-NMR (CDCl<3>) δ 7.39(1H, t), 7.03(1H, d), 6.70(1H, d), 4.12(2H, d), 1.24 (1H, m), 0.59 (2H, m), 0.35(2H, m)[1457] <1>H-NMR (CDCl<3>) δ 7.39(1H, t), 7.03(1H, d), 6.70(1H, d), 4.12(2H, d), 1.24 (1H, m), 0.59 (2H, m), 0.35(2H, m)

[1459] Primer pripreme 233: 2-bromo-6-ciklobutilsulfanil-piridin[1459] Preparation Example 233: 2-bromo-6-cyclobutylsulfanyl-pyridine

[1460] Ciklobutiltiol (0.074 g, 0.84 mmol) i 2,6-dibromopiridin (0.2 g, 0.84 mmol) su izreagovani na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (0.047 g, 22%).[1460] Cyclobutylthiol (0.074 g, 0.84 mmol) and 2,6-dibromopyridine (0.2 g, 0.84 mmol) were reacted in the same manner as in Preparation Example 37 to give the title compound (0.047 g, 22%).

[1461] <1>H-NMR (CDCl<3>) δ 7.27(1H, t), 7.11(1H, d), 7.00(1H, d), 4.28(1H, m), 2.53 (2H, m), 2.08(4H, m)[1461] <1>H-NMR (CDCl<3>) δ 7.27(1H, t), 7.11(1H, d), 7.00(1H, d), 4.28(1H, m), 2.53 (2H, m), 2.08(4H, m)

[1463] Primer pripreme 234: 2-bromo-6-ciklopentilsulfanil-piridin[1463] Preparation Example 234: 2-bromo-6-cyclopentylsulfanyl-pyridine

[1464] Ciklopentantiol (0.09 mL, 0.84 mmol) i 2,6-dibromopiridin (0.2 g, 0.84 mmol) su izreagovani na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (0.2 g, 92%).[1464] Cyclopentanethiol (0.09 mL, 0.84 mmol) and 2,6-dibromopyridine (0.2 g, 0.84 mmol) were reacted in the same manner as in Preparation Example 37 to give the title compound (0.2 g, 92%).

[1465] <1>H-NMR (CDCl<3>) δ 7.27(1H, t), 7.12(1H, d), 7.08(1H, d), 3.98(1H, m), 2.21 (2H, m), 1.76 (2H, m), 1.63(4H, m)[1465] <1>H-NMR (CDCl<3>) δ 7.27(1H, t), 7.12(1H, d), 7.08(1H, d), 3.98(1H, m), 2.21 (2H, m), 1.76 (2H, m), 1.63(4H, m)

[1467] Primer pripreme 235: ciklopropilmetil-(3-jodo-piridin-2-il)-amin[1467] Preparation Example 235: Cyclopropylmethyl-(3-iodo-pyridin-2-yl)-amine

[1468] Nakon što je 2-fluoro-3-jodo-piridin (0.3 g, 1.34 mmol) rastvoren u DMF-u (4 mL),dodati su ciklopropanmetilamin (0.173 mL, 2.02 mmol) i trietilamin (0.186 mL, 1.34 mmol), i mešavina je mešana 18 sati na 110°C. Reaktant je koncentrovan pod smanjenim pritiskom i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.09 g, 24 %).[1468] After 2-fluoro-3-iodo-pyridine (0.3 g, 1.34 mmol) was dissolved in DMF (4 mL), cyclopropanemethylamine (0.173 mL, 2.02 mmol) and triethylamine (0.186 mL, 1.34 mmol) were added, and the mixture was stirred for 18 hours at 110°C. The reactant was concentrated under reduced pressure and purified by column chromatography to give the title compound (0.09 g, 24 %).

[1469] <1>H-NMR (CDCl<3>) δ 8.05 (1H, d), 7.80 (1H, d), 6.29 (1H, m), 5.01 (1H, brs), 3.26 (2H, t), 1.12 (1H, m), 0.54 (2H, m), 0.27 (2H, m)[1469] <1>H-NMR (CDCl<3>) δ 8.05 (1H, d), 7.80 (1H, d), 6.29 (1H, m), 5.01 (1H, brs), 3.26 (2H, t), 1.12 (1H, m), 0.54 (2H, m), 0.27 (2H, m)

[1471] Primer pripreme 236: etil estar 6-(4-bromo-2,6-difluoro-fenilsulfanil)-kapronske kiseline[1471] Preparation example 236: 6-(4-bromo-2,6-difluoro-phenylsulfanyl)-caproic acid ethyl ester

[1472] 4-bromo-2,6-difluoro-benzentiol (0.455 g, 2.02 mmol) dobijen u primeru pripreme 168, NaH (60% u mineralnom ulju, 0.09 g, 2.22 mmol) i etil estar 6-bromo-kapronske kiseline (0.496 g, 2.22 mmol) su izreagovani na isti način kao u primeru pripreme 12 da bi se dobilo naslovno jedinjenje (0.7 g, 94 %).[1472] 4-Bromo-2,6-difluoro-benzenethiol (0.455 g, 2.02 mmol) obtained in Preparation Example 168, NaH (60% in mineral oil, 0.09 g, 2.22 mmol) and 6-bromo-caproic acid ethyl ester (0.496 g, 2.22 mmol) were reacted in the same manner as in Preparation Example 12 to give obtained the title compound (0.7 g, 94 %).

[1473] <1>H-NMR (CDCl<3>) δ 7.10 (2H, d), 4.11 (2H, q), 2.83 (2H, t), 2.26 (2H, t), 1.60 (2H, m), 1.54 (2H, m), 1.42 (2H, m), 1.23 (3H, t).[1473] <1>H-NMR (CDCl<3>) δ 7.10 (2H, d), 4.11 (2H, q), 2.83 (2H, t), 2.26 (2H, t), 1.60 (2H, m), 1.54 (2H, m), 1.42 (2H, m), 1.23 (3H, t).

[1475] Primer pripreme 237: etil estar 6-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-heksanoične kiseline[1475] Preparation Example 237: 6-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-hexanoic acid ethyl ester

[1476] Etil estar 6-(4-bromo-2,6-difluoro-fenilsulfanil)-kapronske kiseline (0.7 g, 1.91 mmol) dobijen u primeru pripreme 236, bis(pinakolato)dibor (0.53 g, 2.10 mmol), kalijumacetat (0.467 g, 4.76 mmol) i dihloro[1,1'-bis(difenilfosfino)ferocen]paladijum(II) (0.14 g, 0.19 mmol) su izreagovani na isti način kao u fazi A primera pripreme 1 da bi se dobilo naslovno jedinjenje (0.4 g, 50%).[1476] 6-(4-Bromo-2,6-difluoro-phenylsulfanyl)-caproic acid ethyl ester (0.7 g, 1.91 mmol) obtained in Preparation Example 236, bis(pinacolato)diboron (0.53 g, 2.10 mmol), potassium acetate (0.467 g, 4.76 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (0.14 g, 0.19 mmol) were reacted in the same manner as in Step A of Preparation Example 1 to give the title compound (0.4 g, 50%).

[1477] <1>H-NMR (CDCl<3>) δ 7.28 (2H, d), 4.12 (2H, q), 2.90 (2H, t), 2.28 (2H, t), 1.64-1.55 (4H, m), 1.45 (2H, m), 1.34 (12H, s), 1.24 (3H, t).[1477] <1>H-NMR (CDCl<3>) δ 7.28 (2H, d), 4.12 (2H, q), 2.90 (2H, t), 2.28 (2H, t), 1.64-1.55 (4H, m), 1.45 (2H, m), 1.34 (12H, s), 1.24 (3H, t).

[1479] Primer pripreme 238: 2-(3,5-difluoro-4-metoksi-fenil)-4,4,5,5-tetrametil-1,3,2-dioksaborolan [0607] 5-bromo-1,3-difluoro-2-metoksi-benzen (1.04 g, 4.66 mmol) je izreagovan na isti način kao u fazi B primera pripreme 2 da bi se dobilo naslovno jedinjenje (0.85 g, 68%).[1479] Preparative Example 238: 2-(3,5-difluoro-4-methoxy-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [0607] 5-Bromo-1,3-difluoro-2-methoxy-benzene (1.04 g, 4.66 mmol) was reacted in the same manner as in Step B of Preparative Example 2 to give the title compound. (0.85 g, 68%).

[1480] <1>H-NMR (CDCl<3>) δ 7.32 (2H, m), 4.03 (3H, s), 1.33 (12H, s)[1480] <1>H-NMR (CDCl<3>) δ 7.32 (2H, m), 4.03 (3H, s), 1.33 (12H, s)

[1482] Primer pripreme 239: 2-ciklopropilsulfanil-3-jodo-piridin[1482] Preparation Example 239: 2-cyclopropylsulfanyl-3-iodo-pyridine

[1483] 2-fluoro-3-jodo-piridin (0.1 g, 0.34 mmol), Cs<2>CO<3>(0.335 g, 1.03 mmol) i ciklopropan tiol (0.02 mL, 0.51 mmol) su izreagovani na isti način kao u primeru pripreme 39 da bi se dobilo naslovno jedinjenje (0.06 g, 63 %).[1483] 2-Fluoro-3-iodo-pyridine (0.1 g, 0.34 mmol), Cs<2>CO<3> (0.335 g, 1.03 mmol) and cyclopropane thiol (0.02 mL, 0.51 mmol) were reacted in the same manner as in Preparation Example 39 to give the title compound (0.06 g, 63%).

[1484] <1>H-NMR (CDCl<3>) δ 8.47(1H, m), 7.90(1H, m), 6.74(1H, m), 2.38(1H, m), 1.10(2H, m), 0.68(2H, m)[1484] <1>H-NMR (CDCl<3>) δ 8.47(1H, m), 7.90(1H, m), 6.74(1H, m), 2.38(1H, m), 1.10(2H, m), 0.68(2H, m)

[1486] Primer pripreme 240: 2-etilsulfanil-3-jodo-piridin[1486] Preparation Example 240: 2-ethylsulfanyl-3-iodo-pyridine

[1487] 2-fluoro-3-jodo-piridin (0.475 g, 2.13 mmol), Cs<2>CO<3>(3.47 g, 10.65 mmol) i etantiol (0.239 mL, 3.19 mmol) su izreagovani na isti način kao u primeru pripreme 39 da bi se dobilo naslovno jedinjenje (0.512 g, 90 %).[1487] 2-Fluoro-3-iodo-pyridine (0.475 g, 2.13 mmol), Cs<2>CO<3> (3.47 g, 10.65 mmol) and ethanethiol (0.239 mL, 3.19 mmol) were reacted in the same manner as in Preparation Example 39 to give the title compound (0.512 g, 90%).

[1488] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.92(1H, m), 6.72(1H, m), 3.16(2H, q), 1.39(3H, t)[1488] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.92(1H, m), 6.72(1H, m), 3.16(2H, q), 1.39(3H, t)

[1490] Primer pripreme 241: 2-butilsulfanil-3-jodo-piridin[1490] Preparation Example 241: 2-butylsulfanyl-3-iodo-pyridine

[1491] 2-fluoro-3-jodo-piridin (0.262 g, 1.17 mmol), Cs<2>CO<3>(1.91 g, 5.87 mmol) i butan tiol (0.189 mL, 1.76 mmol) su izreagovani na isti način kao u primeru pripreme 39 da bi se dobilo naslovno jedinjenje (0.228 g, 66 %).[1491] 2-Fluoro-3-iodo-pyridine (0.262 g, 1.17 mmol), Cs<2>CO<3> (1.91 g, 5.87 mmol) and butane thiol (0.189 mL, 1.76 mmol) were reacted in the same manner as in Preparation Example 39 to give the title compound (0.228 g, 66%).

[1492] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.92(1H, m), 6.71(1H, m), 3.15(2H, t), 1.73(2H, m), 1.50(2H, m), 0.95(3H, t)[1492] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.92(1H, m), 6.71(1H, m), 3.15(2H, t), 1.73(2H, m), 1.50(2H, m), 0.95(3H, t)

[1494] Primer 1: 4-[4-(6-fenoksi-2-piridil)fenoksi]buterna kiselina[1494] Example 1: 4-[4-(6-phenoxy-2-pyridyl)phenoxy]butyric acid

[1495][1495]

[1497] [1497]

[1500] Faza A: etil estar 4-[4-(6-fenoksi-2-piridil)fenoksi]buterne kiseline[1500] Phase A: 4-[4-(6-phenoxy-2-pyridyl)phenoxy]butyric acid ethyl ester

[1501] Etil estar 4-[4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.04 g, 0.12 mmol) dobijen u fazi B primera pripreme 1 i 2-hloro-6-fenoksi-piridin (0.025 g, 0.12 mmol) dobijen u primeru pripreme 126 su rastvoreni u 0.2 mL vodenog rastvora 2M natrijumkarbonata i 0.6 mL 1,4-dioksana, i N<2>gas je dodavan 5 minuta. Dodat je Pd(PPh<3>)<4>(0.014 g, 0.012 mmol) i proizvod je mešan pod refluksom 1 sat. Nakon završetka reakcije, reakcionom rastvoru je dodata voda i ekstrahovan je sa EtOAc da bi se izdvojio organski sloj. Organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.034 g, 75 %).[1501] 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.04 g, 0.12 mmol) obtained in phase B of preparation example 1 and 2-chloro-6-phenoxy-pyridine (0.025 g, 0.12 mmol) obtained in preparation example 126 were dissolved in 0.2 mL aqueous solution of 2M sodium carbonate and 0.6 mL of 1,4-dioxane, and N<2>gas was added for 5 minutes. Pd(PPh<3>)<4> (0.014 g, 0.012 mmol) was added and the product was stirred under reflux for 1 hour. After completion of the reaction, water was added to the reaction solution and extracted with EtOAc to separate the organic layer. The organic layer was dried with MgSO4 and purified by column chromatography to give the title compound (0.034 g, 75 %).

[1502] 1H NMR (CDCl<3>) δ 7.86 (2H, d), 7.68 (1H, t), 7.39 (3H, m), 7.21 (3H, m), 6.90 (2H, d), 6.70 (1H, d), 4.14 (2H, q), 4.04 (2H, t), 2.52 (2H, t), 2.12 (2H, m), 1.26 (3H, t)[1502] 1H NMR (CDCl<3>) δ 7.86 (2H, d), 7.68 (1H, t), 7.39 (3H, m), 7.21 (3H, m), 6.90 (2H, d), 6.70 (1H, d), 4.14 (2H, q), 4.04 (2H, t), 2.52 (2H, t), 2.12 (2H, m), 1.26 (3H, t)

[1503] Faza B: 4-[4-(6-fenoksi-2-piridil)fenoksi]buterne kiseline[1503] Phase B: 4-[4-(6-phenoxy-2-pyridyl)phenoxy]butyric acid

[1504] Etil estar 4-[4-(6-fenoksi-2-piridil)fenoksi]buterne kiseline (0.034 g, 0.09 mmol) dobijen u fazi A je rastvoren u 0.3 mL od svakog THF-a, MeOH-a i IN NaOH vodenog rastvora, i proizvod je mešan 4 sata na sobnoj temperaturi. Nakon završetka reakcije, organski rastvarač je uklonjen, i pH je podešena na 3 upotrebom IN HCl vodenog rastvora. Talog je osušen da bi se dobilo naslovno jedinjenje (0.019 g, 60 %).[1504] 4-[4-(6-phenoxy-2-pyridyl)phenoxy]butyric acid ethyl ester (0.034 g, 0.09 mmol) obtained in step A was dissolved in 0.3 mL of each THF, MeOH, and 1N aqueous NaOH solution, and the product was stirred for 4 hours at room temperature. After completion of the reaction, the organic solvent was removed, and the pH was adjusted to 3 using IN aqueous HCl. The precipitate was dried to give the title compound (0.019 g, 60 %).

[1505] 1H NMR (CDCl<3>) δ 7.86 (2H, d), 7.68 (1H, t), 7.39 (3H, m), 7.21 (3H, m), 6.90 (2H, d), 6.70 (1H, d), 4.05 (2H, t), 2.60 (2H, t), 2.14 (2H, m)[1505] 1H NMR (CDCl<3>) δ 7.86 (2H, d), 7.68 (1H, t), 7.39 (3H, m), 7.21 (3H, m), 6.90 (2H, d), 6.70 (1H, d), 4.05 (2H, t), 2.60 (2H, t), 2.14 (2H, m)

[1507] Primer 2: 4-[2,6-difluoro-4-(6-izopropilsulfanil-2-piridil)fenoksi]buterna kiselina[1507] Example 2: 4-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]butyric acid

[1508][1508]

[1510] [1510]

[1513] Faza A: etil estar 4-[2.6-difluoro-4-(6-izopropilsulfanil-2-piridil)fenoksi]buterne kiseline[1513] Phase A: 4-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]butyric acid ethyl ester

[1514] Etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.06 g, 0.16 mmol) dobijen u fazi C primera pripreme 2 i 2-hloro-6-izopropilsulfanil-piridin (0.037 g, 0.2 mmol) dobijen u primeru pripreme 125 su rastvoreni u 0.24 mL 2M Na<2>CO<3>vodenog rastvora i 1.6 mL 1,4-dioksana, i N<2>gas je dodavan 5 minuta. Dodat je Pd(PPh<3>)<4>(0.018 g, 0.015 mmol) i proizvod je mešan 16 sati pod refluksom. Nakon završetka reakcije, proizvod je razblažen vodom, i organski sloj je izdvojen ekstrakcijom sa EtOAc. Organski sloj je osušen sa MgSO<4>i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.05 g, 78 %).[1514] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.06 g, 0.16 mmol) obtained in phase C of preparation example 2 and 2-chloro-6-isopropylsulfanyl-pyridine (0.037 g, 0.2 mmol) obtained in preparation example 125 were dissolved in 0.24 mL of 2M Na<2>CO<3>aqueous solution and 1.6 mL of 1,4-dioxane, and N<2>gas was added for 5 minutes. Pd(PPh<3>)<4> (0.018 g, 0.015 mmol) was added and the product was stirred for 16 hours under reflux. After completion of the reaction, the product was diluted with water, and the organic layer was separated by extraction with EtOAc. The organic layer was dried with MgSO4 and purified by column chromatography to give the title compound (0.05 g, 78 %).

[1515] 1H NMR (CDCl<3>) δ 7.58 (2H, m), 7.52 (1H, t), 7.31 (1H, d), 7.08 (1H, d), 4.23 (2H, m), 4.16 (2H, q), 4.15 (1H, m), 2.58 (2H, t), 2.11 (2H, m), 1.47 (6H, d), 1.27 (3H, t)[1515] 1H NMR (CDCl<3>) δ 7.58 (2H, m), 7.52 (1H, t), 7.31 (1H, d), 7.08 (1H, d), 4.23 (2H, m), 4.16 (2H, q), 4.15 (1H, m), 2.58 (2H, t), 2.11 (2H, m), 1.47 (6H, d), 1.27 (3H, t)

[1517] Faza B: 4-[2.6-difluoro-4-(6-izopropilsulfanil-2-piridil)fenoksi]buterna kiselina[1517] Phase B: 4-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]butyric acid

[1518] Etil estar 4-[2,6-difluoro-4-(6-izopropilsulfanil-2-piridil)fenoksi]buterne kiseline (50 mg, 0.12 mmol) dobijen u fazi A je rastvoren u svaka 0.4 mL IN NaOH, THF i EtOH, i proizvod je mešan na sobnoj temperaturi 2 sata. Nakon završetka reakcije, organski rastvarač je uklonjen, i pH je podešena na 3 upotrebom IN HCl. Organski sloj je izdvojen i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.04 g, 85 %).[1518] 4-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]butyric acid ethyl ester (50 mg, 0.12 mmol) obtained in step A was dissolved in 0.4 mL each of 1N NaOH, THF, and EtOH, and the product was stirred at room temperature for 2 hours. After completion of the reaction, the organic solvent was removed, and the pH was adjusted to 3 using IN HCl. The organic layer was separated and purified by column chromatography to give the title compound (0.04 g, 85 %).

[1519] 1H NMR (CDCl<3>) δ 7.60 (2H, m), 7.52 (1H, t), 7.31 (1H, d), 7.09 (1H, d), 4.25 (2H, m), 4.13 (1H, m), 2.67 (2H, t), 2.12 (2H, m), 1.47 (6H, d)[1519] 1H NMR (CDCl<3>) δ 7.60 (2H, m), 7.52 (1H, t), 7.31 (1H, d), 7.09 (1H, d), 4.25 (2H, m), 4.13 (1H, m), 2.67 (2H, t), 2.12 (2H, m), 1.47 (6H, d)

[1520] Primer 3: 4-[2,6-difluoro-4-(6-fenoksi-2-piridil)fenoksi]buterna kiselina[1520] Example 3: 4-[2,6-difluoro-4-(6-phenoxy-2-pyridyl)phenoxy]butyric acid

[1521][1521]

[1523] [1523]

[1526] Faza A: etil estar 4-[2,6-difluoro-4-(6-fenoksi-2-piridil)fenoksi]buterne kiseline[1526] Phase A: 4-[2,6-difluoro-4-(6-phenoxy-2-pyridyl)phenoxy]butyric acid ethyl ester

[1527] Etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.032 g, 0.086 mmol) dobijen u fazi C primera pripreme 2 i 2-hloro-6-fenoksi-piridin (0.018 g, 0.087 mmol) dobijen u primeru pripreme 126 su korišćeni da bi reagovali na isti način kao u fazi A primera 1 da bi se dobilo naslovno jedinjenje (0.026 g, 72 %).[1527] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.032 g, 0.086 mmol) obtained in phase C of preparation example 2 and 2-chloro-6-phenoxy-pyridine (0.018 g, 0.087 mmol) obtained in preparation example 126 were used to react in the same manner as in Step A of Example 1 to give the title compound (0.026 g, 72 %).

[1528] 1H NMR (CDCl<3>) δ 7.73 (1H, t), 7.44 (4H, m), 7.36 (1H, d), 7.24 (1H, t), 7.20 (2H, m), 6.81 (1H, d), 4.19 (2H, t), 4.13 (2H, q), 2.56 (2H, t), 2.08 (2H, m), 1.26 (3H, t)[1528] 1H NMR (CDCl<3>) δ 7.73 (1H, t), 7.44 (4H, m), 7.36 (1H, d), 7.24 (1H, t), 7.20 (2H, m), 6.81 (1H, d), 4.19 (2H, t), 4.13 (2H, q), 2.56 (2H, t), 2.08 (2H, m), 1.26 (3H, t)

[1530] Faza B: 4-[2,6-difluoro-4-(6-fenoksi-2-piridil)fenoksi]buterna kiselina[1530] Phase B: 4-[2,6-difluoro-4-(6-phenoxy-2-pyridyl)phenoxy]butyric acid

[1531] Etil estar 4-[2,6-difluoro-4-(6-fenoksi-2-piridil)fenoksi]buterne kiseline (0.025 g, 0.06 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.018 g, 77 %).[1531] 4-[2,6-difluoro-4-(6-phenoxy-2-pyridyl)phenoxy]butyric acid ethyl ester (0.025 g, 0.06 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.018 g, 77%).

[1532] 1H NMR (CDCl<3>) δ 7.72 (1H, t), 7.44 (4H, m), 7.36 (1H, d), 7.24 (1H, t), 7.20 (2H, m), 6.81 (1H, d), 4.21 (2H, t), 2.64 (2H, t), 2.10 (2H, m)[1532] 1H NMR (CDCl<3>) δ 7.72 (1H, t), 7.44 (4H, m), 7.36 (1H, d), 7.24 (1H, t), 7.20 (2H, m), 6.81 (1H, d), 4.21 (2H, t), 2.64 (2H, t), 2.10 (2H, m)

[1534] Primer 4: 4-[2-hloro-4-(6-izopropilsulfanil-2-piridil)fenoksi]buterna kiselina[1534] Example 4: 4-[2-chloro-4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]butyric acid

[1535][1535]

[1537] [1537]

[1540] Etil estar 4-[2-hloro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.052 g, 0.14 mmol) dobijen u fazi B primera pripreme 3 i 2-hloro-6-izopropilsulfanil-piridin (0.026 g, 0.14 mmol) dobijen u primeru pripreme 125 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.012 g, 23 %).[1540] 4-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.052 g, 0.14 mmol) obtained in phase B of preparation example 3 and 2-chloro-6-isopropylsulfanyl-pyridine (0.026 g, 0.14 mmol) obtained in preparation example 125 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.012 g, 23 %).

[1542] 1H NMR (CDCl<3>) δ 8.05 (1H, d), 7.88 (1H, dd), 7.48 (1H, t), 7.32 (1H, d), 7.06 (1H, d), 6.98 (1H, d), 4.16 (2H, t), 4.12 (1H, m), 2.67 (2H, t), 2.20 (2H, m), 1.46 (6H, d)[1542] 1H NMR (CDCl<3>) δ 8.05 (1H, d), 7.88 (1H, dd), 7.48 (1H, t), 7.32 (1H, d), 7.06 (1H, d), 6.98 (1H, d), 4.16 (2H, t), 4.12 (1H, m), 2.67 (2H, t), 2.20 (2H, m), 1.46 (6H, d)

[1543] Primer 5: 4-[2-fluoro-4-(6-izopropilsulfanil-2-piridil)fenoksi]buterna kiselina[1543] Example 5: 4-[2-fluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]butyric acid

[1544][1544]

[1546] [1546]

[1549] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.053 g, 0.15 mmol) dobijen u fazi B primera pripreme 4 i 2-hloro-6-izopropilsulfanil-piridin (0.028 g, 0.15 mmol) dobijen u primeru pripreme 125 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.007 g, 13 %).[1549] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.053 g, 0.15 mmol) obtained in phase B of preparation example 4 and 2-chloro-6-isopropylsulfanyl-pyridine (0.028 g, 0.15 mmol) obtained in preparation example 125 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.007 g, 13 %).

[1550] 1H NMR (CDCl<3>) δ 7.82 (1H, dd), 7.73 (1H, dd), 7.50 (1H, t), 7.33 (1H, d), 7.04 (2H, m), 4.17 (2H, t), 4.11 (1H, m), 2.64 (2H, t), 2.19 (2H, m), 1.47 (6H, d)[1550] 1H NMR (CDCl<3>) δ 7.82 (1H, dd), 7.73 (1H, dd), 7.50 (1H, t), 7.33 (1H, d), 7.04 (2H, m), 4.17 (2H, t), 4.11 (1H, m), 2.64 (2H, t), 2.19 (2H, m), 1.47 (6H, d)

[1552] Primer 6: 4-[4-(6-ciklopentilsulfanil-2-piridil)-2,6-difluoro-fenoksi] buterne kiseline[1552] Example 6: 4-[4-(6-cyclopentylsulfanyl-2-pyridyl)-2,6-difluoro-phenoxy] butyric acid

[1553][1553]

[1555] [1555]

[1558] 2-hloro-6-ciklopentilsulfanil-piridin (0.044 g, 0.2 mmol) dobijen u primeru pripreme 5 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil;-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.068 g, 0.18 mmol) dobijen u fazi C primera pripreme 2 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.008 g, 10 %).[1558] 2-chloro-6-cyclopentylsulfanyl-pyridine (0.044 g, 0.2 mmol) obtained in preparation example 5 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl;-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.068 g, 0.18 mmol) obtained in phase C of preparation example 2 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.008 g, 10 %).

[1559] 1H NMR (CDCl<3>) δ 7.60 (2H, m), 7.50 (1H, t), 7.30 (1H, d), 7.10 (1H, d), 4.26 (2H, t), 4.16 (1H, m), 2.67 (2H, t), 2.24 (2H, m), 2.12 (2H, m), 1.80 (2H, m), 1.70 (4H, m)[1559] 1H NMR (CDCl<3>) δ 7.60 (2H, m), 7.50 (1H, t), 7.30 (1H, d), 7.10 (1H, d), 4.26 (2H, t), 4.16 (1H, m), 2.67 (2H, t), 2.24 (2H, m), 2.12 (2H, m), 1.80 (2H, m), 1.70 (4H, m)

[1561] Primer 7: 4-[4-(2-ciklobutilsulfanil-piridin-3-il)-2-metoksi-fenoksi]-buterna kiselina[1561] Example 7: 4-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2-methoxy-phenoxy]-butyric acid

[1562][1562]

[1564] [1564]

[1567] 2-ciklobutilsulfanil-3-jodo-piridin (0.060 g, 0.21 mmol) dobijen u primeru pripreme 44 i etil estar 4-[2-metoksi-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.075 g, 0.21 mmol) dobijen u primeru pripreme 6 su izreagovani na isti način kao u primeru 1 da bi se dobilo naslovno jedinjenje (0.050 g, 60 %).[1567] 2-cyclobutylsulfanyl-3-iodo-pyridine (0.060 g, 0.21 mmol) obtained in preparation example 44 and 4-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.075 g, 0.21 mmol) obtained in preparation example 6 were reacted at the same way as in Example 1 to obtain the title compound (0.050 g, 60 %).

[1568] 1H NMR (CDCl<3>) δ 8.38 (1H, m), 7.38 (1H, m), 7.02 (1H, m), 6.94 (3H, m), 4.27 (1H, m), 4.14 (2H, t), 3.88(3H, s), 2.66 (2H, t), 2.49(2H, m), 2.21 (2H, m), 2.00 (4H, m)[1568] 1H NMR (CDCl<3>) δ 8.38 (1H, m), 7.38 (1H, m), 7.02 (1H, m), 6.94 (3H, m), 4.27 (1H, m), 4.14 (2H, t), 3.88(3H, s), 2.66 (2H, t), 2.49(2H, m), 2.21 (2H, m), 2.00 (4H, m)

[1570] Primer 8: 4-[2,6-difluoro-4-(2-izopropilsulfanil-4-piridil)fenoksi]buterna kiselina[1570] Example 8: 4-[2,6-difluoro-4-(2-isopropylsulfanyl-4-pyridyl)phenoxy]butyric acid

[1571][1571]

[1573] [1573]

[1576] Faza A: etil estar 4-[2.6-difluoro-4-(2-izopropilsulfanil-4-piridil)fenoksi]buterne kiseline[1576] Phase A: 4-[2,6-difluoro-4-(2-isopropylsulfanyl-4-pyridyl)phenoxy]butyric acid ethyl ester

[1577] 0.7 mL DMF-a je dodato etil estru 4-[4-(2-hloro-4-piridil)-2,6-difluoro-fenoksi]buterne kiseline (0.025 g, 0.07 mmol) dobijenom u primeru pripreme 7, Cs<2>CO<3>(0.046 g, 0.14 mmol) i 2-propantiol (0.013 mL, 0.14 mmol), i proizvod je mešan 4 sata na 80°C. Reakcioni rastvor je koncentrovan pod smanjenim pritiskom i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.007 g, 25 %).[1577] 0.7 mL of DMF was added to 4-[4-(2-chloro-4-pyridyl)-2,6-difluoro-phenoxy]butyric acid ethyl ester (0.025 g, 0.07 mmol) obtained in Preparation Example 7, Cs<2>CO<3> (0.046 g, 0.14 mmol) and 2-propanethiol (0.013 mL, 0.14 mmol), and the product was stirred for 4 hours at 80°C. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give the title compound (0.007 g, 25 %).

[1578] 1H NMR (CDCl<3>) δ 8.43 (1H, d), 7.46 (1H, d), 7.34 (1H, dd), 7.32 (1H, m), 7.18 (1H, m), 4.20 (2H, t), 4.17 (3H, m), 2.63 (2H, t), 2.13 (2H, m), 1.34 (6H, d), 1.28 (3H, t)[1578] 1H NMR (CDCl<3>) δ 8.43 (1H, d), 7.46 (1H, d), 7.34 (1H, dd), 7.32 (1H, m), 7.18 (1H, m), 4.20 (2H, t), 4.17 (3H, m), 2.63 (2H, t), 2.13 (2H, m), 1.34 (6H, d), 1.28 (3H, t)

[1580] Faza B: 4-[2,6-difluoro-4-(2-izopropilsulfanil-4-piridil)fenoksi]buterna kiselina[1580] Phase B: 4-[2,6-difluoro-4-(2-isopropylsulfanyl-4-pyridyl)phenoxy]butyric acid

[1581] Etil estar 4-[2,6-difluoro-4-(2-izopropilsulfanil-4-piridil)fenoksi]buterne kiseline (0.007 g, 0.018 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.004 g, 55 %).[1581] 4-[2,6-difluoro-4-(2-isopropylsulfanyl-4-pyridyl)phenoxy]butyric acid ethyl ester (0.007 g, 0.018 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.004 g, 55%).

[1582] 1H NMR (CDCl<3>) δ 8.43 (1H, d), 7.46 (1H, d), 7.35 (1H, m), 7.32 (1H, m), 7.20 (1H, dd), 4.21 (2H, t), 3.55 (1H, m), 2.73 (2H, t), 2.15 (2H, m), 1.35 (6H, d)[1582] 1H NMR (CDCl<3>) δ 8.43 (1H, d), 7.46 (1H, d), 7.35 (1H, m), 7.32 (1H, m), 7.20 (1H, dd), 4.21 (2H, t), 3.55 (1H, m), 2.73 (2H, t), 2.15 (2H, m), 1.35 (6H, d)

[1584] Primer 9: 4-[4-[6-(ciklopentoksi)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina[1584] Example 9: 4-[4-[6-(cyclopentoxy)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid

[1585][1585]

[1587] [1587]

[1590] Faza A: etil estar 4-[4-[6-(ciklopentoksi)-2-piridil]-2,6-difluoro-fenoksi]buterne kiseline[1590] Phase A: 4-[4-[6-(cyclopentoxy)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid ethyl ester

[1591] 2-hloro-6-(ciklopentoksi)piridin (0.055 g, 0.27 mmol) dobijen u primeru pripreme 8 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil;-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.068 g, 0.18 mmol) dobijen u fazi C primera pripreme 2 su izreagovani na isti način kao u fazi A primera 1 da bi se dobilo naslovno jedinjenje (0.051 g, 68 %).[1591] 2-chloro-6-(cyclopentoxy)pyridine (0.055 g, 0.27 mmol) obtained in preparation example 8 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl;-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.068 g, 0.18 mmol) obtained in phase C of preparation example 2 were reacted in the same manner as in step A of Example 1 to give the title compound (0.051 g, 68 %).

[1592] 1H NMR (CDCl<3>) δ 7.58 (3H, m), 7.18 (1H, d), 6.63 (1H, d), 5.50 (1H, m), 4.22 (2H, t), 4.16 (2H, m), 2.58 (2H, t), 2.12 (2H, m), 2.06 (2H, m), 1.82 (4H, m), 1.65 (2H, m), 1.27 (3H, t)[1592] 1H NMR (CDCl<3>) δ 7.58 (3H, m), 7.18 (1H, d), 6.63 (1H, d), 5.50 (1H, m), 4.22 (2H, t), 4.16 (2H, m), 2.58 (2H, t), 2.12 (2H, m), 2.06 (2H, m), 1.82 (4H, m), 1.65 (2H, m), 1.27 (3H, t)

[1594] Faza B: 4-[4-[6-(ciklopentoksi)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina[1594] Phase B: 4-[4-[6-(cyclopentoxy)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid

[1595] Etil estar 4-[4-[6-(ciklopentoksi)-2-piridil]-2,6-difluoro-fenoksi]buterne kiseline (0.05 g, 0.12 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.023 g, 50 %).[1595] 4-[4-[6-(cyclopentoxy)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid ethyl ester (0.05 g, 0.12 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.023 g, 50%).

[1596] 1H NMR (CDCl<3>) δ 7.59 (3H, m), 7.18 (1H, d), 6.63 (1H, d), 5.50 (1H, m), 4.24 (2H, t), 2.67 (2H, t), 2.14 (2H, m), 2.04 (2H, m), 1.82 (4H, m), 1.65 (2H, m)[1596] 1H NMR (CDCl<3>) δ 7.59 (3H, m), 7.18 (1H, d), 6.63 (1H, d), 5.50 (1H, m), 4.24 (2H, t), 2.67 (2H, t), 2.14 (2H, m), 2.04 (2H, m), 1.82 (4H, m), 1.65 (2H, m)

[1598] Primer 10: 4-[4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-dimetil-fenoksi]-buterna kiselina[1598] Example 10: 4-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-dimethyl-phenoxy]-butyric acid

[1599][1599]

[1601] [1601]

[1604] 2-ciklobutilsulfanil-3-jodo-piridin (0.048 g, 0.16 mmol) dobijen u primeru pripreme 44 i etil estar 4-[2,6-dimetil-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.060 g, 0.16 mmol) dobijen u primeru pripreme 11 su izreagovani na isti način kao u primeru 1 da bi se dobilo naslovno jedinjenje (0.040 g, 61 %).[1604] 2-cyclobutylsulfanyl-3-iodo-pyridine (0.048 g, 0.16 mmol) obtained in preparation example 44 and 4-[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.060 g, 0.16 mmol) obtained in preparation example 11 were reacted in the same manner as in Example 1 to give the title compound (0.040 g, 61 %).

[1605] 1H NMR (CDCl<3>) δ 8.37 (1H, m), 7.33 (1H, m), 7.05 (2H, s), 6.99 (1H, m), 4.42 (1H, m), 3.89 (2H, t), 2.71 (2H, t), 2.49 (2H, m), 2.30 (6H, s), 2.18 (2H, m), 2.07 (4H, m)[1605] 1H NMR (CDCl<3>) δ 8.37 (1H, m), 7.33 (1H, m), 7.05 (2H, s), 6.99 (1H, m), 4.42 (1H, m), 3.89 (2H, t), 2.71 (2H, t), 2.49 (2H, m), 2.30 (6H, s), 2.18 (2H, m), 2.07 (4H, m)

[1607] Primer 11: 4-[4-[3-(ciklopentoksi)fenil]-2,6-difluoro-fenoksi]buterna kiselina[1607] Example 11: 4-[4-[3-(cyclopentoxy)phenyl]-2,6-difluoro-phenoxy]butyric acid

[1608][1608]

[1610] [1610]

[1613] 1-bromo-3-(ciklopentoksi)benzen (0.04 g, 0.16 mmol) dobijen u primeru pripreme 9 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil;-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.05 g, 0.13 mmol) dobijen u fazi C primera pripreme 2 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.01 g, 20 %).[1613] 1-Bromo-3-(cyclopentoxy)benzene (0.04 g, 0.16 mmol) obtained in Preparation Example 9 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl;-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.05 g, 0.13 mmol) obtained in Phase C of Preparation Example 2 were used to reacted in the same manner as in steps A and B of Example 1 to give the title compound (0.01 g, 20 %).

[1614] 1H NMR (CDCl<3>) δ 7.30 (1H, t), 7.11 (2H, m), 7.04 (1H, d), 7.00 (1H, m), 6.87 (1H, dd), 4.81 (1H, m), 4.22 (2H, t), 2.65 (2H, t), 2.12 (2H, m), 1.95 (2H, m), 1.88 (2H, m), 1.82 (2H, m), 1.64 (2H, m)[1614] 1H NMR (CDCl<3>) δ 7.30 (1H, t), 7.11 (2H, m), 7.04 (1H, d), 7.00 (1H, m), 6.87 (1H, dd), 4.81 (1H, m), 4.22 (2H, t), 2.65 (2H, t), 2.12 (2H, m), 1.95 (2H, m), 1.88 (2H, m), 1.82 (2H, m), 1.64 (2H, m)

[1616] Primer 12: 4-[2,6-difluoro-4-(6-pirolidin-1-il-2-piridil)fenoksi]buterna kiselina[1616] Example 12: 4-[2,6-difluoro-4-(6-pyrrolidin-1-yl-2-pyridyl)phenoxy]butyric acid

[1617][1617]

[1619] [1619]

[1622] 2-hloro-6-pirolidin-1-il-piridin (0.028 g, 0.15 mmol) dobijen u primeru pripreme 10 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil;-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.051 g, 0.13 mmol) dobijen u fazi C primera pripreme 2 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje(0.006 g, 13 %).[1622] 2-chloro-6-pyrrolidin-1-yl-pyridine (0.028 g, 0.15 mmol) obtained in preparation example 10 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl;-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.051 g, 0.13 mmol) obtained in phase C of preparation example 2 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.006 g, 13 %).

[1623] 1H NMR (CDCl<3>) δ 7.62 (2H, m), 7.46 (1H, t), 6.90 (1H, d), 6.32 (1H, d), 4.20 (2H, t), 3.53 (4H, t), 2.65 (2H, t), 2.12 (2H, t), 2.01 (4H, m)[1623] 1H NMR (CDCl<3>) δ 7.62 (2H, m), 7.46 (1H, t), 6.90 (1H, d), 6.32 (1H, d), 4.20 (2H, t), 3.53 (4H, t), 2.65 (2H, t), 2.12 (2H, t), 2.01 (4H, m)

[1625] Primer 13: 4-[4-(2-sec-butilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina[1625] Example 13: 4-[4-(2-sec-butylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid

[1626][1626]

[1628] [1628]

[1631] Butain-2-tiol (27 mg, 0.29 mmol) i etil estar 4-[2,6-difluoro-4-(2-fluoro-3-piridil)fenoksi]buterne kiseline (100 mg, 0.29 mmol) dobijen u primeru pripreme 109 su korišćeni da bi sekvencijalno reagovali na isti način kao u primeru pripreme 5 i fazi B primera 1 da bi se dobilo naslovno jedinjenje (65 mg, 54 %).[1631] Butane-2-thiol (27 mg, 0.29 mmol) and 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butyric acid ethyl ester (100 mg, 0.29 mmol) obtained in Preparative Example 109 were used to react sequentially in the same manner as in Preparative Example 5 and Phase B of Example 1 to give the title compound (65 mg, 54 %).

[1632] 1H NMR (CDCl<3>) δ 8.43 (1H, m), 7.32 (1H, m), 7.01 (3H, m), 4.26 (2H, t), 3.96 (1H, m), 2.69 (2H, t), 2.14 (2H, m), 1.73 (2H, m), 1.33 (3H, d), 1.00 (3H, t)[1632] 1H NMR (CDCl<3>) δ 8.43 (1H, m), 7.32 (1H, m), 7.01 (3H, m), 4.26 (2H, t), 3.96 (1H, m), 2.69 (2H, t), 2.14 (2H, m), 1.73 (2H, m), 1.33 (3H, d), 1.00 (3H, t)

[1634] Primer 14: 4-[4-[3-(ciklopentoksi)fenil]-2,3-difluoro-fenoksi]buterna kiselina[1634] Example 14: 4-[4-[3-(cyclopentoxy)phenyl]-2,3-difluoro-phenoxy]butyric acid

[1635][1635]

[1637] [1637]

[1638] Faza A: etil estar 4-[4-[3-(ciklopentoksi)fenil]-2.3-difluoro-fenoksi]buterna kiselina[1638] Phase A: 4-[4-[3-(cyclopentoxy)phenyl]-2,3-difluoro-phenoxy]butyric acid ethyl ester

[1639] 1.5 mL acetonitrila je dodat u etil estar 4-[2,3-difluoro-4-(3-hidroksifenil)fenoksi]buterne kiseline (0.089 g, 0.26 mmol) dobijen u primeru pripreme 13, ciklopentil bromid (0.034 g, 0.31 mmol) i K<2>CO<3>(0.036 g, 0.26 mmol), i proizvod su 16 sati mešani pod refluksom. Nakon završetka reakcije, reakcioni rastvor je koncentrovan pod smanjenim pritiskom i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.042 g, 39 %).[1639] 1.5 mL of acetonitrile was added to 4-[2,3-difluoro-4-(3-hydroxyphenyl)phenoxy]butyric acid ethyl ester (0.089 g, 0.26 mmol) obtained in Preparation Example 13, cyclopentyl bromide (0.034 g, 0.31 mmol) and K<2>CO<3> (0.036 g, 0.26 mmol), and the product was stirred for 16 h. stirred under reflux. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by column chromatography to give the title compound (0.042 g, 39 %).

[1640] 1H NMR (CDCl<3>) δ 7.31 (1H, t), 7.10 (1H, m), 7.04 (1H, dd), 7.00 (1H, d), 6.88 (1H, dd), 6.78 (1H, m), 4.79 (1H, m), 4.15 (4H, m), 2.55 (2H, t), 2.16 (2H, m), 1.92 (4H, m), 1.80 (2H, m), 1.62 (2H, m), 1.27 (3H, t)[1640] 1H NMR (CDCl<3>) δ 7.31 (1H, t), 7.10 (1H, m), 7.04 (1H, dd), 7.00 (1H, d), 6.88 (1H, dd), 6.78 (1H, m), 4.79 (1H, m), 4.15 (4H, m), 2.55 (2H, t), 2.16 (2H, m), 1.92 (4H, m), 1.80 (2H, m), 1.62 (2H, m), 1.27 (3H, t)

[1642] Faza B: 4-[4-[3-(ciklopentoksi)fenil]-2,3-difluoro-fenoksi]buterna kiselina[1642] Phase B: 4-[4-[3-(cyclopentoxy)phenyl]-2,3-difluoro-phenoxy]butyric acid

[1643] Etil estar 4-[4-[3-(ciklopentoksi)fenil]-2,3-difluoro-fenoksi]buterne kiseline (0.041 g, 0.1 mmol) dobijen u fazi A je rastvoren u po 0.5 mL EtOH i NaOH (1M vodeni rastvor), i proizvod je mešan na sobnoj temperaturi 1 sat. Nakon završetka reakcije, dodat je EtOAc , i vodeni sloj je podešen na pH 4 upotrebom IN HCl vodenim rastvorom. Organski sloj je izdvojen i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.036 g, 96 %).[1643] 4-[4-[3-(cyclopentoxy)phenyl]-2,3-difluoro-phenoxy]butyric acid ethyl ester (0.041 g, 0.1 mmol) obtained in phase A was dissolved in 0.5 mL each of EtOH and NaOH (1M aqueous solution), and the product was stirred at room temperature for 1 hour. After the reaction was complete, EtOAc was added, and the aqueous layer was adjusted to pH 4 using IN aqueous HCl. The organic layer was separated and purified by column chromatography to give the title compound (0.036 g, 96 %).

[1644] 1H NMR (CDCl<3>) δ 7.31 (1H, t), 7.09 (1H, m), 7.04 (1H, dd), 7.00 (1H, d), 6.88 (1H, dd), 6.78 (1H, dd), 4.79 (1H, m), 4.15 (2H, t), 2.63 (2H, t), 2.18 (2H, m), 1.90 (4H, m), 1.81 (2H, m), 1.62 (2H, m)[1644] 1H NMR (CDCl<3>) δ 7.31 (1H, t), 7.09 (1H, m), 7.04 (1H, dd), 7.00 (1H, d), 6.88 (1H, dd), 6.78 (1H, dd), 4.79 (1H, m), 4.15 (2H, t), 2.63 (2H, t), 2.18 (2H, m), 1.90 (4H, m), 1.81 (2H, m), 1.62 (2H, m)

[1646] Primer 15: 4-[2,6-difluoro-4-[6-(1-piperidil)-2-piridil]fenoksi]buterna kiselina[1646] Example 15: 4-[2,6-difluoro-4-[6-(1-piperidyl)-2-pyridyl]phenoxy]butyric acid

[1647][1647]

[1649] [1649]

[1651] 2-hloro-6-(1-piperidil)piridin (0.09 g, 0.45 mmol) dobijen u primeru pripreme 14 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil;-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.154 g, 0.41 mmol) dobijen u fazi C primera pripreme 2 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.06 g, 39 %).[1651] 2-chloro-6-(1-piperidyl)pyridine (0.09 g, 0.45 mmol) obtained in preparation example 14 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl;-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.154 g, 0.41 mmol) obtained in phase C of preparation example 2 are used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.06 g, 39 %).

[1652] 1H NMR (CDCl<3>) δ 7.56 (2H, m), 7.49 (1H, t), 6.92 (1H, d), 6.60 (1H, d), 4.22 (2H, t), 3.61 (4H, brs), 2.64 (2H, t), 2.10 (2H, m), 1.67 (6H, brs)[1652] 1H NMR (CDCl<3>) δ 7.56 (2H, m), 7.49 (1H, t), 6.92 (1H, d), 6.60 (1H, d), 4.22 (2H, t), 3.61 (4H, brs), 2.64 (2H, t), 2.10 (2H, m), 1.67 (6H, brs)

[1653] Primer 16: 4-[4-(6-anilino-2-piridil)-2,6-difluoro-fenoksi]buterna kiselina[1653] Example 16: 4-[4-(6-anilino-2-pyridyl)-2,6-difluoro-phenoxy]butyric acid

[1654][1654]

[1656] [1656]

[1659] 6-hloro-N-fenil-piridin-2-amin (0.09 g, 0.44 mmol) dobijen u primeru pripreme 15 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil;-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.148 g, 0.4 mmol) dobijen u fazi C primera pripreme 2 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.037 g, 24 %).[1659] 6-chloro-N-phenyl-pyridin-2-amine (0.09 g, 0.44 mmol) obtained in preparation example 15 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl;-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.148 g, 0.4 mmol) obtained in phase C of preparation example 2 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.037 g, 24 %).

[1660] 1H NMR (CDCl<3>) δ 7.54 (3H, m), 7.37 (4H, m), 7.08 (2H, m), 6.83 (1H, brs), 6.82 (1H, d), 4.24 (2H, t), 2.66 (2H, t), 2.11 (2H, m)[1660] 1H NMR (CDCl<3>) δ 7.54 (3H, m), 7.37 (4H, m), 7.08 (2H, m), 6.83 (1H, brs), 6.82 (1H, d), 4.24 (2H, t), 2.66 (2H, t), 2.11 (2H, m)

[1662] Primer 17: 4-[2,6-difluoro-4-[6-(N-metilanilino)-2-piridil]fenoksi] buterna kiselina[1662] Example 17: 4-[2,6-difluoro-4-[6-(N-methylanilino)-2-pyridyl]phenoxy]butyric acid

[1663][1663]

[1665] [1665]

[1667] Faza A: metil estar 4-[2.6-difluoro-4-[6-(N-metilanilino)-2-piridil]fenoksi]buterne kiseline[1667] Phase A: 4-[2,6-difluoro-4-[6-(N-methylanilino)-2-pyridyl]phenoxy]butyric acid methyl ester

[1668] 4-[4-(6-anilino-2-piridil)-2,6-difluoro-fenoksi]buterna kiselina (0.033 g, 0.085 mmol) dobijena u primeru 16 je rastvorena u 1 mL DMF-a, i dodati su kalijum tert-butoksid (0.036 g, 0.34 mmol) i jodometan (0.02 mL, 0.34 mmol). Proizvod je mešan na sobnoj temperaturi 16 sati. Nakon završetka reakcije, reakcioni rastvor je koncentrovan pod smanjenim pritiskom i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.02 g, 57 %).[1668] 4-[4-(6-anilino-2-pyridyl)-2,6-difluoro-phenoxy]butyric acid (0.033 g, 0.085 mmol) obtained in Example 16 was dissolved in 1 mL of DMF, and potassium tert-butoxide (0.036 g, 0.34 mmol) and iodomethane (0.02 mL, 0.34 mmol) were added. The product was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by column chromatography to give the title compound (0.02 g, 57 %).

[1669] 1H NMR (CDCl<3>) δ 7.63 (2H, m), 7.42 (2H, m), 7.36 (1H, t), 7.30 (2H, m), 7.24 (1H, m), 6.98 (1H, d), 6.48 (1H, d), 4.22 (2H, t), 3.70 (3H, s), 3.57 (3H, s), 2.62 (2H, t), 2.11 (2H, m)[1669] 1H NMR (CDCl<3>) δ 7.63 (2H, m), 7.42 (2H, m), 7.36 (1H, t), 7.30 (2H, m), 7.24 (1H, m), 6.98 (1H, d), 6.48 (1H, d), 4.22 (2H, t), 3.70 (3H, s), 3.57 (3H, s), 2.62 (2H, t), 2.11 (2H, m)

[1671] Faza B: 4-[2,6-difluoro-4-[6-(N-metilanilino)-2-piridil]fenoksi]buterna kiselina[1671] Phase B: 4-[2,6-difluoro-4-[6-(N-methylanilino)-2-pyridyl]phenoxy]butyric acid

[1672] Metil estar 4-[2,6-difluoro-4-[6-(N-metilanilino)-2-piridil]fenoksi]buterne kiseline (0.02 g, 0.048 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.013 g, 66 %).[1672] 4-[2,6-difluoro-4-[6-(N-methylanilino)-2-pyridyl]phenoxy]butyric acid methyl ester (0.02 g, 0.048 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.013 g, 66%).

[1673] 1H NMR (CDCl<3>) δ 7.62 (2H, m), 7.42 (2H, m), 7.36 (1H, m), 7.30 (2H, m), 7.24 (1H, m), 6.98 (1H, d), 6.48 (1H, d), 4.21 (2H, t), 3.58 (3H, s), 2.67 (2H, t), 2.12 (2H, m)[1673] 1H NMR (CDCl<3>) δ 7.62 (2H, m), 7.42 (2H, m), 7.36 (1H, m), 7.30 (2H, m), 7.24 (1H, m), 6.98 (1H, d), 6.48 (1H, d), 4.21 (2H, t), 3.58 (3H, s), 2.67 (2H, t), 2.12 (2H, m)

[1674] Primer 18: 4-[4-[6-(ciklopentilamino)-2-piridil]-2,6-difluoro-fenoksi] buterna kiselina[1674] Example 18: 4-[4-[6-(cyclopentylamino)-2-pyridyl]-2,6-difluoro-phenoxy] butyric acid

[1675][1675]

[1677] [1677]

[1680] Faza A: etil estar 4-[4-[6-(ciklopentilamino)-2-piridil]-2.6-difluoro-fenoksi]buterne kiseline [0681] 6-hloro-N-ciklopentil-piridin-2-amin (0.05 g, 0.25 mmol) dobijen u primeru pripreme 16 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil;-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.06 g, 0.16 mmol) dobijen u fazi C primera pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 1 da bi se dobilo naslovno jedinjenje (0.03 g, 48 %).[1680] Phase A: 4-[4-[6-(cyclopentylamino)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid ethyl ester [0681] 6-chloro-N-cyclopentyl-pyridin-2-amine (0.05 g, 0.25 mmol) obtained in Preparation Example 16 and ethyl ester 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl;-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid (0.06 g, 0.16 mmol) obtained in Step C of Preparative Example 2 was used to react in the same manner as in Step A of Example 1 to give the title compound (0.03 g, 48%).

[1681] 1H NMR (CDCl<3>) δ 7.50 (2H, m), 7.46 (1H, t), 6.90 (1H, d), 6.35 (1H, d), 4.65 (1H, d), 4.20 (2H, t), 4.15 (2H, q), 4.05 (1H, m), 2.58 (2H, t), 2.08 (4H, m), 1.76 (2H, m), 1.66 (2H, m), 1.52 (2H, m), 1.26 (3H, t)[1681] 1H NMR (CDCl<3>) δ 7.50 (2H, m), 7.46 (1H, t), 6.90 (1H, d), 6.35 (1H, d), 4.65 (1H, d), 4.20 (2H, t), 4.15 (2H, q), 4.05 (1H, m), 2.58 (2H, t), 2.08 (4H, m), 1.76 (2H, m), 1.66 (2H, m), 1.52 (2H, m), 1.26 (3H, t)

[1683] Faza B: 4-[4-[6-(ciklopentilamino)-2-piridil]-2.6-difluoro-fenoksi]buterna kiselina[1683] Phase B: 4-[4-[6-(cyclopentylamino)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid

[1684] Etil estar 4-[4-[6-(ciklopentilamino)-2-piridil]-2,6-difluoro-fenoksi]buterne kiseline (0.03 g, 0.07 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.026 g, 93 %).[1684] 4-[4-[6-(cyclopentylamino)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid ethyl ester (0.03 g, 0.07 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.026 g, 93%).

[1685] 1H NMR (CDCl<3>) δ 7.47 (3H, m), 6.87 (1H, d), 6.36 (1H, d), 4.22 (2H, t), 4.02 (1H, m), 2.64 (2H, t), 2.10 (4H, m), 1.78 (2H, m), 1.65 (2H, m), 1.52 (2H, m)[1685] 1H NMR (CDCl<3>) δ 7.47 (3H, m), 6.87 (1H, d), 6.36 (1H, d), 4.22 (2H, t), 4.02 (1H, m), 2.64 (2H, t), 2.10 (4H, m), 1.78 (2H, m), 1.65 (2H, m), 1.52 (2H, m)

[1687] Primer 19: 4-[4-[6-(ciklopropilmetilsulfanil)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina [0685][1687] Example 19: 4-[4-[6-(cyclopropylmethylsulfanyl)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid [0685]

[1689] [1689]

[1692] 2-hloro-6-(ciklopropilmetilsulfanil)piridin (0.033 g, 0.16 mmol) dobijen u fazi B primera pripreme 18 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil;-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.05 g, 0.135 mmol) dobijen u fazi C primera pripreme 2 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.03 g, 58 %).[1692] 2-chloro-6-(cyclopropylmethylsulfanyl)pyridine (0.033 g, 0.16 mmol) obtained in phase B of preparation example 18 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl;-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.05 g, 0.135 mmol) obtained in phase C of example Preparation 2 was used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.03 g, 58 %).

[1693] 1H NMR (CDCl<3>) δ 7.58 (2H, m), 7.52 (1H, t), 7.30 (1H, d), 7.14 (1H, d), 4.25 (2H, t), 3.22 (2H, d), 2.67 (2H, t), 2.12 (2H, m), 1.21 (1H, m), 0.62 (2H, m), 0.36 (2H, m)[1693] 1H NMR (CDCl<3>) δ 7.58 (2H, m), 7.52 (1H, t), 7.30 (1H, d), 7.14 (1H, d), 4.25 (2H, t), 3.22 (2H, d), 2.67 (2H, t), 2.12 (2H, m), 1.21 (1H, m), 0.62 (2H, m), 0.36 (2H, m)

[1694] Primer 20: 4-[4-(6-ciklobutilsulfanil-2-piridil)-2,6-difluoro-fenoksi] buterna kiselina[1694] Example 20: 4-[4-(6-cyclobutylsulfanyl-2-pyridyl)-2,6-difluoro-phenoxy] butyric acid

[1695][1695]

[1697] [1697]

[1700] 2-hloro-6-ciklobutilsulfanil-piridin (0.033 g, 0.165 mmol) dobijen u primeru pripreme 19 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil;-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.05 g, 0.135 mmol) dobijen u fazi C primera pripreme 2 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.035 g, 68 %).[1700] 2-chloro-6-cyclobutylsulfanyl-pyridine (0.033 g, 0.165 mmol) obtained in preparation example 19 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl;-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.05 g, 0.135 mmol) obtained in phase C of preparation example 2 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.035 g, 68 %).

[1701] 1H NMR (CDCl<3>) δ 7.58 (2H, m), 7.52 (1H, t), 7.30 (1H, d), 7.04 (1H, d), 4.42 (1H, m), 4.25 (2H, t), 2.68 (2H, t), 2.60 (2H, m), 2.12 (6H, m)[1701] 1H NMR (CDCl<3>) δ 7.58 (2H, m), 7.52 (1H, t), 7.30 (1H, d), 7.04 (1H, d), 4.42 (1H, m), 4.25 (2H, t), 2.68 (2H, t), 2.60 (2H, m), 2.12 (6H, m)

[1703] Primer 21: 4-[2,6-difluoro-4-(6-propilsulfanil-2-piridil)fenoksi]buterna kiselina[1703] Example 21: 4-[2,6-difluoro-4-(6-propylsulfanyl-2-pyridyl)phenoxy]butyric acid

[1704][1704]

[1706] [1706]

[1709] 2-hloro-6-propilsulfanil-piridin (0.03 g, 0.16 mmol) dobijen u primeru pripreme 20 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil;-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.05 g, 0.135 mmol) dobijen u fazi C primera pripreme 2 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.037 g, 75 %).[1709] 2-chloro-6-propylsulfanyl-pyridine (0.03 g, 0.16 mmol) obtained in preparation example 20 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl;-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.05 g, 0.135 mmol) obtained in phase C of preparation example 2 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.037 g, 75 %).

[1710] 1H NMR (CDCl<3>) δ 7.58 (2H, m), 7.52 (1H, t), 7.30 (1H, d), 7.12 (1H, d), 4.25 (2H, t), 3.23 (2H, t), 2.67 (2H, t), 2.12 (2H, m), 1.81 (2H, m), 1.08 (3H, t)[1710] 1H NMR (CDCl<3>) δ 7.58 (2H, m), 7.52 (1H, t), 7.30 (1H, d), 7.12 (1H, d), 4.25 (2H, t), 3.23 (2H, t), 2.67 (2H, t), 2.12 (2H, m), 1.81 (2H, m), 1.08 (3H, t)

[1712] Primer 22: 4-[2,6-difluoro-4-(6-izopropoksi-2-piridil)fenoksi]buterna kiselina[1712] Example 22: 4-[2,6-difluoro-4-(6-isopropoxy-2-pyridyl)phenoxy]butyric acid

[1713][1713]

[1715] [1715]

[1718] Faza A: etil estar 4-[2,6-difluoro-4-(6-izopropoksi-2-piridil)fenoksi]buterna kiselina[1718] Phase A: 4-[2,6-difluoro-4-(6-isopropoxy-2-pyridyl)phenoxy]butyric acid ethyl ester

[1719] 2-hloro-6-izopropoksi-piridin (0.03 g, 0.17 mmol) dobijen u primeru pripreme 21 i etil estar 4[1719] 2-chloro-6-isopropoxy-pyridine (0.03 g, 0.17 mmol) obtained in preparation example 21 and ethyl ester 4

[1720] [2,6-difluoro-4-(4,4,5,5-tetrametil;-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.05 g, 0.135 mmol) dobijen u fazi C primera pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 1 da bi se dobilo naslovno jedinjenje (0.038 g, 74 %).[1720] [2,6-Difluoro-4-(4,4,5,5-tetramethyl;-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid (0.05 g, 0.135 mmol) obtained in Step C of Preparation Example 2 was used to react in the same manner as in Step A of Example 1 to give the title compound (0.038 g, 74%).

[1721] 1H NMR (CDCl<3>) δ 7.57 (3H, m), 7.19 (1H, d), 6.63 (1H, d), 5.44 (1H, m), 4.22 (2H, t), 4.16 (2H, q), 2.59 (2H, t), 2.10 (2H, m), 1.40 (6H, d), 1.27 (3H, t)[1721] 1H NMR (CDCl<3>) δ 7.57 (3H, m), 7.19 (1H, d), 6.63 (1H, d), 5.44 (1H, m), 4.22 (2H, t), 4.16 (2H, q), 2.59 (2H, t), 2.10 (2H, m), 1.40 (6H, d), 1.27 (3H, t)

[1723] Faza B: 4-[2,6-difluoro-4-(6-izopropoksi-2-piridil)fenoksi]buterna kiselina[1723] Phase B: 4-[2,6-difluoro-4-(6-isopropoxy-2-pyridyl)phenoxy]butyric acid

[1724] Etil estar 4-[2,6-difluoro-4-(6-izopropoksi-2-piridil)fenoksi]buterne kiseline (0.037 g, 0.1 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.03 g, 88 %).[1724] 4-[2,6-difluoro-4-(6-isopropoxy-2-pyridyl)phenoxy]butyric acid ethyl ester (0.037 g, 0.1 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.03 g, 88%).

[1725] 1H NMR (CDCl<3>) δ 7.61 (1H, t), 7.56 (2H, m), 7.19 (1H, d), 6.63 (1H, d), 5.44 (1H, m), 4.24 (2H, t), 2.67 (2H, t), 2.11 (2H, m), 1.40 (6H, d)[1725] 1H NMR (CDCl<3>) δ 7.61 (1H, t), 7.56 (2H, m), 7.19 (1H, d), 6.63 (1H, d), 5.44 (1H, m), 4.24 (2H, t), 2.67 (2H, t), 2.11 (2H, m), 1.40 (6H, d)

[1727] Primer 23: 4-[2,6-difluoro-4-(6-propoksi-2-piridil)fenoksi]buterna kiselina[1727] Example 23: 4-[2,6-difluoro-4-(6-propoxy-2-pyridyl)phenoxy]butyric acid

[1728][1728]

[1730] [1730]

[1733] Faza A: etil estar 4-[2,6-difluoro-4-(6-propoksi-2-piridil)fenoksi]buterna kiselina[1733] Phase A: 4-[2,6-difluoro-4-(6-propoxy-2-pyridyl)phenoxy]butyric acid ethyl ester

[1734] 2-hloro-6-propoksi-piridin (0.03 g, 0.17 mmol) dobijen u primeru pripreme 22 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil;-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.05 g, 0.135 mmol) dobijen u fazi C primera pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 1 da bi se dobilo naslovno jedinjenje (0.026 g, 40 %).[1734] 2-Chloro-6-propoxy-pyridine (0.03 g, 0.17 mmol) obtained in Preparation Example 22 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl;-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.05 g, 0.135 mmol) obtained in Phase C of Preparation Example 2 were used to would react in the same way as in phase A of Example 1 to give the title compound (0.026 g, 40 %).

[1735] 1H NMR (CDCl<3>) δ 7.62 (1H, t), 7.58 (2H, m), 7.21 (1H, d), 6.69 (1H, d), 4.35 (2H, t), 4.22 (2H, t), 4.16 (2H, q), 2.59 (2H, t), 2.10 (2H, m), 1.84 (2H, m), 1.27 (3H, t), 1.06 (3H, t)[1735] 1H NMR (CDCl<3>) δ 7.62 (1H, t), 7.58 (2H, m), 7.21 (1H, d), 6.69 (1H, d), 4.35 (2H, t), 4.22 (2H, t), 4.16 (2H, q), 2.59 (2H, t), 2.10 (2H, m), 1.84 (2H, m), 1.27 (3H, t), 1.06 (3H, t)

[1737] Faza B: 4-[2,6-difluoro-4-(6-propoksi-2-piridil)fenoksi]buterna kiselina[1737] Phase B: 4-[2,6-difluoro-4-(6-propoxy-2-pyridyl)phenoxy]butyric acid

[1738] Etil estar 4-[2,6-difluoro-4-(6-propoksi-2-piridil)fenoksi]buterne kiseline (0.026 g, 0.068 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje(0.018 g, 81 %).[1738] 4-[2,6-difluoro-4-(6-propoxy-2-pyridyl)phenoxy]butyric acid ethyl ester (0.026 g, 0.068 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.018 g, 81%).

[1739] 1H NMR (CDCl<3>) δ 7.60 (1H, t), 7.58 (2H, m), 7.21 (1H, d), 6.68 (1H, d), 4.35 (2H, t), 4.24 (2H, t), 2.67 (2H, t), 2.11 (2H, m), 1.83 (2H, m), 1.06 (3H, t)[1739] 1H NMR (CDCl<3>) δ 7.60 (1H, t), 7.58 (2H, m), 7.21 (1H, d), 6.68 (1H, d), 4.35 (2H, t), 4.24 (2H, t), 2.67 (2H, t), 2.11 (2H, m), 1.83 (2H, m), 1.06 (3H, t)

[1740] Primer 24: 4-[4-[6-(ciklopropilmetoksi)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina[1740] Example 24: 4-[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid

[1741][1741]

[1743] [1743]

[1745] Faza A: etil estar 4-[4-[6-(ciklopropilmetoksi)-2-piridil]-2.6-difluoro-fenoksi]buterne kiseline [0705] 2-hloro-6-(ciklopropilmetoksi)-piridin (0.033 g, 0.18 mmol) dobijen u primeru pripreme 23 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil;-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.05 g, 0.135 mmol) dobijen u fazi C primera pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 1 da bi se dobilo naslovno jedinjenje(0.050 g, 95 %).[1745] Phase A: 4-[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid ethyl ester [0705] 2-chloro-6-(cyclopropylmethoxy)-pyridine (0.033 g, 0.18 mmol) obtained in Preparation Example 23 and ethyl ester 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl;-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid (0.05 g, 0.135 mmol) obtained in Step C of Preparation Example 2 was used to react in the same manner as in Step A of Example 1 to give the title compound (0.050 g, 95%).

[1746] 1H NMR (CDCl<3>) δ 7.61 (1H, t), 7.57 (2H, m), 7.21 (1H, d), 6.72 (1H, d), 4.22 (4H, m), 4.16 (2H, q), 2.58 (2H, t), 2.10 (2H, m), 1.33 (1H, m), 1.26 (3H, t), 0.64 (2H, m), 0.39 (2H, m)[1746] 1H NMR (CDCl<3>) δ 7.61 (1H, t), 7.57 (2H, m), 7.21 (1H, d), 6.72 (1H, d), 4.22 (4H, m), 4.16 (2H, q), 2.58 (2H, t), 2.10 (2H, m), 1.33 (1H, m), 1.26 (3H, t), 0.64 (2H, m), 0.39 (2H, m)

[1748] Faza B: 4-[4-[6-(ciklopropilmetoksi)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina[1748] Phase B: 4-[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid

[1749] Etil estar 4-[4-[6-(ciklopropilmetoksi)-2-piridil]-2,6-difluoro-fenoksi]buterne kiseline (0.05 g, 0.127 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.034 g, 73 %).[1749] 4-[4-[6-(Cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid ethyl ester (0.05 g, 0.127 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.034 g, 73%).

[1750] 1H NMR (CDCl<3>) δ 7.62 (1H, t), 7.57 (2H, m), 7.21 (1H, d), 6.73 (1H, d), 4.23 (4H, m), 2.67 (2H, t), 2.11 (2H, m), 1.33 (1H, m), 0.64 (2H, m), 0.39 (2H, m)[1750] 1H NMR (CDCl<3>) δ 7.62 (1H, t), 7.57 (2H, m), 7.21 (1H, d), 6.73 (1H, d), 4.23 (4H, m), 2.67 (2H, t), 2.11 (2H, m), 1.33 (1H, m), 0.64 (2H, m), 0.39 (2H, m)

[1752] Primer 25: 4-[4-[6-(ciklobutoksi)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina[1752] Example 25: 4-[4-[6-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid

[1753][1753]

[1755] [1755]

[1758] Faza A: etil estar 4-[4-[6-(ciklobutoksi)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina[1758] Phase A: 4-[4-[6-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid ethyl ester

[1759] 2-hloro-6-(ciklobutoksi)-piridin (0.033 g, 0.18 mmol) dobijen u primeru pripreme 24 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil;-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.05 g, 0.135 mmol) dobijen u fazi C primera pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 1 da bi se dobilo naslovno jedinjenje (0.042 g, 80 %).[1759] 2-chloro-6-(cyclobutoxy)-pyridine (0.033 g, 0.18 mmol) obtained in preparation example 24 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl;-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.05 g, 0.135 mmol) obtained in phase C of preparation example 2 were used to react in the same manner as in Step A of Example 1 to give the title compound (0.042 g, 80 %).

[1760] 1H NMR (CDCl<3>) δ 7.61 (1H, t), 7.56 (2H, m), 7.21 (1H, d), 6.65 (1H, d), 5.26 (1H, m), 4.22 (2H, t), 4.15 (2H, q), 2.60 (2H, t), 2.52 (2H, m), 2.19 (2H, m), 2.10 (2H, m), 1.87 (1H, m), 1.76 (1H, m), 1.27 (3H, t) Faza B: 4-[4-[6-(ciklobutoksi)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina[1760] 1H NMR (CDCl<3>) δ 7.61 (1H, t), 7.56 (2H, m), 7.21 (1H, d), 6.65 (1H, d), 5.26 (1H, m), 4.22 (2H, t), 4.15 (2H, q), 2.60 (2H, t), 2.52 (2H, m), 2.19 (2H, m), 2.10 (2H, m), 1.87 (1H, m), 1.76 (1H, m), 1.27 (3H, t) Phase B: 4-[4-[6-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid

[1761] Etil estar 4-[4-[6-(ciklobutoksi)-2-piridil]-2,6-difluoro-fenoksi]buterne kiseline (0.042 g, 0.1 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.024 g, 61 %).[1761] 4-[4-[6-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid ethyl ester (0.042 g, 0.1 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.024 g, 61%).

[1762] 1H NMR (CDCl<3>) δ 7.61 (1H, t), 7.56 (2H, m), 7.21 (1H, d), 6.65 (1H, d), 5.25 (1H, m), 4.24 (2H, t), 2.67 (2H, t), 2.52 (2H, m), 2.19 (2H, m), 2.11 (2H, m), 1.87 (1H, m), 1.76 (1H, m)[1762] 1H NMR (CDCl<3>) δ 7.61 (1H, t), 7.56 (2H, m), 7.21 (1H, d), 6.65 (1H, d), 5.25 (1H, m), 4.24 (2H, t), 2.67 (2H, t), 2.52 (2H, m), 2.19 (2H, m), 2.11 (2H, m), 1.87 (1H, m), 1.76 (1H, m)

[1764] Primer 26: 4-[4-[6-(ciklobutoksi)-2-piridil]-2-metil-fenoksi]buterna kiselina[1764] Example 26: 4-[4-[6-(cyclobutoxy)-2-pyridyl]-2-methyl-phenoxy]butyric acid

[1765][1765]

[1767] [1767]

[1770] Faza A: etil estar 4-[4-[6-(ciklobutoksi)-2-piridil]-2-metil-fenoksi]buterne kiseline[1770] Phase A: 4-[4-[6-(cyclobutoxy)-2-pyridyl]-2-methyl-phenoxy]butyric acid ethyl ester

[1771] 2-hloro-6-(ciklobutoksi)-piridin (0.041 g, 0.22 mmol) dobijen u primeru pripreme 24 i etil estar 4-[2-metil-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.059 g, 0.17 mmol) dobijen u fazi C primera pripreme 25 su korišćeni da bi reagovali na isti način kao u fazi A primera 1 da bi se dobilo naslovno jedinjenje (0.031 g, 49 %).[1771] 2-Chloro-6-(cyclobutoxy)-pyridine (0.041 g, 0.22 mmol) obtained in Preparation Example 24 and 4-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.059 g, 0.17 mmol) obtained in Phase C of Preparation Example 25 were used to would react in the same way as in phase A of Example 1 to give the title compound (0.031 g, 49 %).

[1772] 1H NMR (CDCl<3>) δ 7.80 (2H, m), 7.57 (1H, t), 7.25 (1H, d), 6.86 (1H, d), 6.56 (1H, d), 5.56 (1H, m), 4.15 (2H, q), 4.06 (2H, t), 2.56 (2H, t), 2.54 (2H, m), 2.28 (3H, s), 2.18 (2H, m), 2.16 (2H, m), 1.87 (1H, m), 1.74 (1H, m), 1.27 (3H, t)[1772] 1H NMR (CDCl<3>) δ 7.80 (2H, m), 7.57 (1H, t), 7.25 (1H, d), 6.86 (1H, d), 6.56 (1H, d), 5.56 (1H, m), 4.15 (2H, q), 4.06 (2H, t), 2.56 (2H, t), 2.54 (2H, m), 2.28 (3H, s), 2.18 (2H, m), 2.16 (2H, m), 1.87 (1H, m), 1.74 (1H, m), 1.27 (3H, t)

[1774] Faza B: 4-[4-[6-(ciklobutoksi)-2-piridil]-2-metil-fenoksi]buterna kiselina[1774] Phase B: 4-[4-[6-(cyclobutoxy)-2-pyridyl]-2-methyl-phenoxy]butyric acid

[1775] Etil estar 4-[4-[6-(ciklobutoksi)-2-piridil]-2-metil-fenoksi]buterne kiseline (0.031 g, 0.08 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.013 g, 45 %).[1775] 4-[4-[6-(cyclobutoxy)-2-pyridyl]-2-methyl-phenoxy]butyric acid ethyl ester (0.031 g, 0.08 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.013 g, 45%).

[1776] 1H NMR (CDCl<3>) δ 7.80 (2H, m), 7.56 (1H, t), 7.24 (1H, d), 6.87 (1H, d), 6.56 (1H, d), 5.25 (1H, m), 4.08 (2H, t), 2.63 (2H, t), 2.52 (2H, m), 2.28 (3H, s), 2.18 (4H, m), 1.87 (1H, m), 1.72 (1H, m)[1776] 1H NMR (CDCl<3>) δ 7.80 (2H, m), 7.56 (1H, t), 7.24 (1H, d), 6.87 (1H, d), 6.56 (1H, d), 5.25 (1H, m), 4.08 (2H, t), 2.63 (2H, t), 2.52 (2H, m), 2.28 (3H, s), 2.18 (4H, m), 1.87 (1H, m), 1.72 (1H, m)

[1778] Primer 27: 4-[4-[6-(ciklobutoksi)-2-piridil]-2-(trifluorometil)fenoksi] buterna kiselina[1778] Example 27: 4-[4-[6-(cyclobutoxy)-2-pyridyl]-2-(trifluoromethyl)phenoxy] butyric acid

[1779][1779]

[1781] [1781]

[1782] Faza A: etil estar 4-[4-16-(ciklobutoksi)-2-piridil]-2-(trifluorometil)fenoksi]buterne kiseline[1782] Phase A: 4-[4-16-(cyclobutoxy)-2-pyridyl]-2-(trifluoromethyl)phenoxy]butyric acid ethyl ester

[1783] 2-hloro-6-(ciklobutoksi)-piridin (0.035 g, 0.19 mmol) dobijen u primeru pripreme 24 i etil estar 4-[4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)-2-(trifluorometil)fenoksi]buterne kiseline (0.061 g, 0.15 mmol) dobijen u fazi C primera pripreme 26 su korišćeni da bi reagovali na isti način kao u fazi A primera 1 da bi se dobilo naslovno jedinjenje (0.041 g, 63 %).[1783] 2-chloro-6-(cyclobutoxy)-pyridine (0.035 g, 0.19 mmol) obtained in preparation example 24 and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy]butyric acid ethyl ester (0.061 g, 0.15 mmol) obtained in phase C of preparation example 26 were used to react in the same manner as in Step A of Example 1 to give the title compound (0.041 g, 63 %).

[1784] 1H NMR (CDCl<3>) δ 8.24 (1H, d), 8.13 (1H, dd), 7.61 (1H, t), 7.25 (1H, m), 7.05 (1H, dd), 6.62 (1H, d), 5.25 (1H, m), 4.15 (4H, m), 2.57 (4H, m), 2.17 (4H, m), 1.87 (1H, m), 1.74 (1H, m), 1.26 (3H, t)[1784] 1H NMR (CDCl<3>) δ 8.24 (1H, d), 8.13 (1H, dd), 7.61 (1H, t), 7.25 (1H, m), 7.05 (1H, dd), 6.62 (1H, d), 5.25 (1H, m), 4.15 (4H, m), 2.57 (4H, m), 2.17 (4H, m), 1.87 (1H, m), 1.74 (1H, m), 1.26 (3H, t)

[1786] Faza B: 4-[4-[6-(ciklobutoksi)-2-piridil]-2-(trifluorometil)fenoksi]buterna kiselina[1786] Phase B: 4-[4-[6-(cyclobutoxy)-2-pyridyl]-2-(trifluoromethyl)phenoxy]butyric acid

[1787] Etil estar 4-[4-[6-(ciklobutoksi)-2-piridil]-2-(trifluorometil)fenoksi]buterne kiseline (0.04 g, 0.09 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.03 g, 84 %).[1787] 4-[4-[6-(cyclobutoxy)-2-pyridyl]-2-(trifluoromethyl)phenoxy]butyric acid ethyl ester (0.04 g, 0.09 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.03 g, 84%).

[1788] 1H NMR (CDCl<3>) δ 8.24 (1H, d), 8.12 (1H, dd), 7.60 (1H, t), 7.26 (1H, d), 7.04 (1H, m), 6.62 (1H, d), 5.25 (1H, m), 4.17 (2H, t), 2.65 (2H, m), 2.52 (2H, m), 2.20 (4H, m), 1.87 (1H, m), 1.73 (1H, m)[1788] 1H NMR (CDCl<3>) δ 8.24 (1H, d), 8.12 (1H, dd), 7.60 (1H, t), 7.26 (1H, d), 7.04 (1H, m), 6.62 (1H, d), 5.25 (1H, m), 4.17 (2H, t), 2.65 (2H, m), 2.52 (2H, m), 2.20 (4H, m), 1.87 (1H, m), 1.73 (1H, m)

[1790] Primer 28: 4-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi] valerijanska kiselina[1790] Example 28: 4-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy] valeric acid

[1791][1791]

[1793] [1793]

[1796] Faza A: metil estar 4-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]valerijanske kiseline [0725] Metil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]valerijanske kiseline (0.053 g, 0.14 mmol) dobijen u fazi C primera pripreme 27 i 2-ciklobutilsulfanil-3-jodo-piridin (0.045 g, 0.15 mmol) dobijen u fazi B primera pripreme 44 su rastvoreni u 0.7 mL 1,2-dimetoksietana i Na<2>CO<3>(2M vodeni rastvor, 0.21 mL, 0.43 mmol), i N<2>gas je dodavan 5 minuta. Dodat je PdCl<2>(PPh<3>)<2>(0.005 g, 0.007 mmol), i proizvod je mešan 3 sata na 80°C. Nakon završetka reakcije, reakcioni rastvor je dodat sa 3 mL vode i ekstrahovan sa EtOAc. Organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.046 g, 79 %).[1796] Phase A: 4-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]valeric acid methyl ester [0725] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]valeric acid methyl ester (0.053 g, 0.14 mmol) was obtained in phase A. C of preparation example 27 and 2-cyclobutylsulfanyl-3-iodo-pyridine (0.045 g, 0.15 mmol) obtained in step B of preparation example 44 were dissolved in 0.7 mL of 1,2-dimethoxyethane and Na<2>CO<3> (2M aqueous solution, 0.21 mL, 0.43 mmol), and N<2> gas was added for 5 minutes. PdCl<2>(PPh<3>)<2> (0.005 g, 0.007 mmol) was added, and the product was stirred for 3 hours at 80°C. After completion of the reaction, the reaction solution was added with 3 mL of water and extracted with EtOAc. The organic layer was dried with MgSO4 and purified by column chromatography to give the title compound (0.046 g, 79 %).

[1797] 1H NMR (CDCl<3>) δ 8.41 (1H, m), 7.33 (1H, m), 7.01 (3H, m), 4.41 (2H, m), 3.69 (3H, s), 2.63 (2H, t), 2.51 (2H, m), 2.05 (6H, m), 1.33 (3H, d)[1797] 1H NMR (CDCl<3>) δ 8.41 (1H, m), 7.33 (1H, m), 7.01 (3H, m), 4.41 (2H, m), 3.69 (3H, s), 2.63 (2H, t), 2.51 (2H, m), 2.05 (6H, m), 1.33 (3H, d)

[1799] Faza B: 4-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]valerijanska kiselina[1799] Phase B: 4-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]valeric acid

[1800] Metil estar 4-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]valerijanske kiseline (0.069 g, 0.17 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.045 g, 67 %).[1800] 4-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]valeric acid methyl ester (0.069 g, 0.17 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.045 g, 67%).

[1801] 1H NMR (CDCl<3>) δ 8.41 (1H, m), 7.33 (1H, m), 7.00 (3H, m), 4.41 (2H, m), 2.71 (2H, t), 2.52 (2H, m), 2.05 (6H, m), 1.35 (3H, d)[1801] 1H NMR (CDCl<3>) δ 8.41 (1H, m), 7.33 (1H, m), 7.00 (3H, m), 4.41 (2H, m), 2.71 (2H, t), 2.52 (2H, m), 2.05 (6H, m), 1.35 (3H, d)

[1803] Primer 29: 4-[4-[6-(ciklobutoksi)-2-piridil]-2,6-difluoro-fenoksi] valerijanska kiselina[1803] Example 29: 4-[4-[6-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenoxy] valeric acid

[1804][1804]

[1806] [1806]

[1809] Faza A: metil estar 4-[4-[6-(ciklobutoksi)-2-piridil]-2,6-difluoro-fenoksi]valerijanske kiseline [0730] Metil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]valerijanske kiseline (0.04 g, 0.11 mmol) dobijen u fazi C primera pripreme 27 i 2-hloro-6-(ciklobutoksi)-piridin(0.02 g, 0.11 mmol) dobijen u primeru pripreme 24 su rastvoreni u 1 mL 1,2-dimetoksietana i Na<2>CO<3>(2M vodeni rastvor, 0.16 mL, 0.32 mmol), i N<2>gas je dodavan 5 minuta. Dodat je Pd(PPh<3>)<4>(0.011 g, 0.01 mmol), i proizvod je 2 sata mešan na 80°C. Nakon završetka reakcije, reakcioni rastvor je dodat sa 3 mL vode i ekstrahovan sa EtOAc. Organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.028 g, 66 %).[1809] Phase A: 4-[4-[6-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenoxy]valeric acid methyl ester [0730] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]valeric acid methyl ester (0.04 g, 0.11 mmol) obtained in phase C of Example preparation 27 and 2-chloro-6-(cyclobutoxy)-pyridine (0.02 g, 0.11 mmol) obtained in preparation example 24 were dissolved in 1 mL of 1,2-dimethoxyethane and Na<2>CO<3> (2M aqueous solution, 0.16 mL, 0.32 mmol), and N<2> gas was added over 5 minutes. Pd(PPh<3>)<4> (0.011 g, 0.01 mmol) was added, and the product was stirred at 80°C for 2 hours. After completion of the reaction, the reaction solution was added with 3 mL of water and extracted with EtOAc. The organic layer was dried with MgSO4 and purified by column chromatography to give the title compound (0.028 g, 66 %).

[1810] 1H NMR (CDCl<3>) δ 7.58 (3H, m), 7.22 (1H, d), 6.66 (1H, d), 5.26 (1H, m), 4.38 (1H, m), 3.70 (3H, s), 2.64 (2H, t), 2.53 (2H, m), 2.19 (2H, m), 2.03 (2H, m), 1.89 (1H, m), 1.74 (1H, m), 1.31 (3H, d)[1810] 1H NMR (CDCl<3>) δ 7.58 (3H, m), 7.22 (1H, d), 6.66 (1H, d), 5.26 (1H, m), 4.38 (1H, m), 3.70 (3H, s), 2.64 (2H, t), 2.53 (2H, m), 2.19 (2H, m), 2.03 (2H, m), 1.89 (1H, m), 1.74 (1H, m), 1.31 (3H, d)

[1812] Faza B: 4-[4-[6-(ciklobutoksi)-2-piridil]-2.6-difluoro-fenoksi]valerijanska kiselina[1812] Phase B: 4-[4-[6-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenoxy]valeric acid

[1813] Metil estar 4-[4-[6-(ciklobutoksi)-2-piridil]-2,6-difluoro-fenoksi]valerijanske kiseline (0.027 g, 0.07 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.02 g, 76 %).[1813] 4-[4-[6-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenoxy]valeric acid methyl ester (0.027 g, 0.07 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.02 g, 76%).

[1814] 1H NMR (CDCl<3>) δ 7.60 (3H, m), 7.21 (1H, d), 6.65 (1H, d), 5.26 (1H, m), 4.40 (1H, m), 2.70 (2H, t), 2.53 (2H, m), 2.20 (2H, m), 2.05 (2H, m), 1.86 (1H, m), 1.76 (1H, m), 1.32 (3H, d)[1814] 1H NMR (CDCl<3>) δ 7.60 (3H, m), 7.21 (1H, d), 6.65 (1H, d), 5.26 (1H, m), 4.40 (1H, m), 2.70 (2H, t), 2.53 (2H, m), 2.20 (2H, m), 2.05 (2H, m), 1.86 (1H, m), 1.76 (1H, m), 1.32 (3H, d)

[1816] Primer 30: 4-[[5-(2-ciklobutilsulfanil-3-piridil)-2-piridil]oksi]valerijanska kiselina[1816] Example 30: 4-[[5-(2-cyclobutylsulfanyl-3-pyridyl)-2-pyridyl]oxy]valeric acid

[1817][1817]

[1819] [1819]

[1820] Faza A: metil estar 4-[[5-(2-ciklobutilsulfanil-3-piridil)-2-piridil]oksi]valerijanske kiseline[1820] Phase A: 4-[[5-(2-cyclobutylsulfanyl-3-pyridyl)-2-pyridyl]oxy]valeric acid methyl ester

[1821] 0.6 mL 1,2-dimetoksietana je dodato u metil estar 4-[[5-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)-2-piridil]oksi]valerijanske kiseline (0.038 g, 0.11 mmol) dobijene u fazi B primera pripreme 28, 2-ciklobutilsulfanil-3-jodo-piridin (0.033 g, 0.11 mmol) dobijen u fazi B primera pripreme 44 i Na<2>CO<3>(2M vodeni rastvor, 0.17 mL, 0.34 mmol), i N<2>gas je dodavan 5 minuta. Dodat je PdCl<2>(PPh<3>)<2>(0.004 g, 0.005 mmol),i proizvod je mešan 16 sati na 80°C. Reaktantu je dodata voda i ekstrahovan je sa EtOAc. Organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.006 g, 14 %).[1821] 0.6 mL of 1,2-dimethoxyethane was added to 4-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]valeric acid methyl ester (0.038 g, 0.11 mmol) obtained in phase B of preparation example 28, 2-cyclobutylsulfanyl-3-iodo-pyridine. (0.033 g, 0.11 mmol) obtained in Step B of Preparation Example 44 and Na<2>CO<3>(2M aqueous solution, 0.17 mL, 0.34 mmol), and N<2>gas was added for 5 minutes. PdCl<2>(PPh<3>)<2> (0.004 g, 0.005 mmol) was added, and the product was stirred for 16 hours at 80°C. Water was added to the reactant and extracted with EtOAc. The organic layer was dried with MgSO4 and purified by column chromatography to give the title compound (0.006 g, 14 %).

[1822] 1H NMR (CDCl<3>) δ 8.40 (1H, m), 8.12 (1H, m), 7.66 (1H, m), 7.35 (1H, m), 7.05 (1H, m), 6.73 (1H, d), 5.29 (1H, m), 4.43 (1H, m), 3.67 (3H, s), 2.50 (4H, m), 2.04 (6H, m), 1.37 (3H, d)[1822] 1H NMR (CDCl<3>) δ 8.40 (1H, m), 8.12 (1H, m), 7.66 (1H, m), 7.35 (1H, m), 7.05 (1H, m), 6.73 (1H, d), 5.29 (1H, m), 4.43 (1H, m), 3.67 (3H, s), 2.50 (4H, m), 2.04 (6H, m), 1.37 (3H, d)

[1824] Faza B: 4-[[5-(2-ciklobutilsulfanil-3-piridil)-2-piridil]oksi]valerijanska kiselina[1824] Phase B: 4-[[5-(2-cyclobutylsulfanyl-3-pyridyl)-2-pyridyl]oxy]valeric acid

[1825] Metil estar 4-[[5-(2-ciklobutilsulfanil-3-piridil)-2-piridil]oksi]valerijanske kiseline (0.006 g, 0.016 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.005 g, 90 %).[1825] 4-[[5-(2-cyclobutylsulfanyl-3-pyridyl)-2-pyridyl]oxy]valeric acid methyl ester (0.006 g, 0.016 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.005 g, 90%).

[1826] 1H NMR (MeOH-d<4>) δ 8.56 (1H, m), 8.33 (1H, m), 8.17 (1H, m), 7.98 (1H, m), 7.55 (1H, m), 7.33 (1H, d), 5.23 (1H, m), 4.36 (1H, m), 2.53 (2H, m), 2.46 (2H, m), 2.05 (6H, m), 1.42 (3H, d)[1826] 1H NMR (MeOH-d<4>) δ 8.56 (1H, m), 8.33 (1H, m), 8.17 (1H, m), 7.98 (1H, m), 7.55 (1H, m), 7.33 (1H, d), 5.23 (1H, m), 4.36 (1H, m), 2.53 (2H, m), 2.46 (2H, m), 2.05 (6H, m), 1.42 (3H, d)

[1828] Primer 31: 4-{2,6-difluoro-4-[2-(3-metil-butilsulfanil)-piridin-3-il]-fenoksi}-buterna kiselina[1828] Example 31: 4-{2,6-difluoro-4-[2-(3-methyl-butylsulfanyl)-pyridin-3-yl]-phenoxy}-butyric acid

[1829][1829]

[1831] [1831]

[1834] Etil estar 3-metil-butan-1-tiol (31 mg, 0.29 mmol) i 4-[2,6-difluoro-4-(2-fluoro-3-piridil)fenoksi]buterne kiseline (100 mg, 0.29 mmol) dobijen u primeru pripreme 109 su korišćeni da bi sekvencijalno reagovali na isti način kao u primeru pripreme 5 i fazi B primera 1 da bi se dobilo naslovno jedinjenje (75 mg, 60 %).[1834] 3-Methyl-butane-1-thiol (31 mg, 0.29 mmol) and 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butyric acid (100 mg, 0.29 mmol) obtained in Preparative Example 109 were used to react sequentially in the same manner as in Preparative Example 5 and Step B of Example 1 to give the title compound (75 mg, 60 %).

[1835] 1H NMR (CDCl<3>) δ 8.43 (1H, m), 7.33 (1H, m), 7.03 (3H, m), 4.26 (2H, t), 3.18 (2H, t), 2.69 (2H, t), 2.14 (2H, m), 1.70 (1H, m), 1.56 (2H, m), 0.93 (6H, d)[1835] 1H NMR (CDCl<3>) δ 8.43 (1H, m), 7.33 (1H, m), 7.03 (3H, m), 4.26 (2H, t), 3.18 (2H, t), 2.69 (2H, t), 2.14 (2H, m), 1.70 (1H, m), 1.56 (2H, m), 0.93 (6H, d)

[1836] Primer 32: 4-{2,6-difluoro-4-[2-(2-fluoro-etoksi)-piridin-3-il]-fenoksi}-buterna kiselina[1836] Example 32: 4-{2,6-difluoro-4-[2-(2-fluoro-ethoxy)-pyridin-3-yl]-phenoxy}-butyric acid

[1837][1837]

[1839] [1839]

[1842] 2-fluoro-etanol (29 mg, 0.45 mmol) i 4-[2,6-difluoro-4-(2-fluoro-3-piridil)fenoksi]buterne kiseline (70 mg, 0.22 mmol) dobijen u primeru pripreme 56 su korišćeni da bi reagovali na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (5 mg, 6 %).[1842] 2-Fluoro-ethanol (29 mg, 0.45 mmol) and 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butyric acid (70 mg, 0.22 mmol) obtained in Preparative Example 56 were used to react in the same manner as in Preparative Example 37 to give the title compound (5 mg, 6%).

[1843] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.61 (1H, m), 7.18 (2H, m), 6.99 (1H, m), 4.80 (1H, m), 4.69 (1H, m), 4.67 (1H, m), 4.62 (1H, m), 4.25 (2H, t), 2.69 (2H, t), 2.13 (2H, m)[1843] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.61 (1H, m), 7.18 (2H, m), 6.99 (1H, m), 4.80 (1H, m), 4.69 (1H, m), 4.67 (1H, m), 4.62 (1H, m), 4.25 (2H, t), 2.69 (2H, t), 2.13 (2H, m)

[1845] Primer 33: 2-[1-[[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]metil]ciklopropil ]sirćetna kiselina[1845] Example 33: 2-[1-[[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]methyl]cyclopropyl]acetic acid

[1846][1846]

[1848] [1848]

[1851] Faza A: 2-[1-[[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]metil]ciklopropil]acetonitril [0746] 2-ciklobutilsulfanil-3-jodo-piridin (0.064 g, 0.22 mmol) dobijen u fazi B primera pripreme 44 i 2-[1-[[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]metil]ciklopropil]acetonitril (0.092 g, 0.26 mmol) dobijen u fazi E primera pripreme 30 su rastvoreni u 2 mL 1,2-dimetoksietana i Na<2>CO<3>(2M vodeni rastvor, 0.33 mL, 0.66 mmol), i N<2>gas je dodavan 5 minuta. Dodat je PdCl<2>(PPh<3>)<2>(0.008 g, 0.011 mmol), i proizvod je mešan 2 sata na 80°C. Reaktantu je dodata voda i ekstrahovan je sa EtOAc. Organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.043 g, 50 %).[1851] Phase A: 2-[1-[[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]methyl]cyclopropyl]acetonitrile [0746] 2-cyclobutylsulfanyl-3-iodo-pyridine (0.064 g, 0.22 mmol) obtained in Phase B of Preparation Example 44 and 2-[1-[[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]cyclopropyl]acetonitrile (0.092 g, 0.26 mmol) obtained in step E of Preparation Example 30 was dissolved in 2 mL of 1,2-dimethoxyethane and Na<2>CO<3> (2M aqueous solution, 0.33 mL). 0.66 mmol), and N<2> gas was added for 5 minutes. PdCl<2>(PPh<3>)<2> (0.008 g, 0.011 mmol) was added, and the product was stirred for 2 hours at 80°C. Water was added to the reactant and extracted with EtOAc. The organic layer was dried with MgSO4 and purified by column chromatography to give the title compound (0.043 g, 50 %).

[1852] 1H NMR (CDCl<3>) δ 8.41 (1H, m), 7.33 (1H, m), 7.00 (3H, m), 4.42 (1H, m), 4.06 (2H, s), 2.77 (2H, s), 2.51 (2H, m), 2.04 (4H, m), 0.77 (4H, m)[1852] 1H NMR (CDCl<3>) δ 8.41 (1H, m), 7.33 (1H, m), 7.00 (3H, m), 4.42 (1H, m), 4.06 (2H, s), 2.77 (2H, s), 2.51 (2H, m), 2.04 (4H, m), 0.77 (4H, m)

[1854] Faza B: 2-[1-[[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]metil] ciklopropil]sirćetna kiselina[1854] Phase B: 2-[1-[[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]methyl]cyclopropyl]acetic acid

[1856] 2-[1-[[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]metil]ciklopropil] acetonitril (0.042 g, 0.108 mmol) dobijen u fazi A je rastvoren u 1 mL etanola, i dodat je NaOH (6M vodeni rastvor, 0.11 mL, 6.6 mmol). Proizvod je mešan 16 sati na 100°C. pH je podešena na 3 upotrebom HCl vodenog rastvora, i reaktant je zatim ekstrahovan sa EtOAc. Organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.008 g, 18 %).[1856] 2-[1-[[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]methyl]cyclopropyl] acetonitrile (0.042 g, 0.108 mmol) obtained in step A was dissolved in 1 mL of ethanol, and NaOH (6M aqueous solution, 0.11 mL, 6.6 mmol) was added. The product was mixed for 16 hours at 100°C. The pH was adjusted to 3 using aqueous HCl, and the reactant was then extracted with EtOAc. The organic layer was dried with MgSO4 and purified by column chromatography to give the title compound (0.008 g, 18 %).

[1857] 1H NMR (CDCl<3>) δ 8.41 (1H, m), 7.32 (1H, m), 6.98 (3H, m), 4.41 (1H, m), 4.11 (2H, s), 2.66 (2H, s), 2.52 (2H, m), 2.04 (4H, m), 0.66 (4H, m)[1857] 1H NMR (CDCl<3>) δ 8.41 (1H, m), 7.32 (1H, m), 6.98 (3H, m), 4.41 (1H, m), 4.11 (2H, s), 2.66 (2H, s), 2.52 (2H, m), 2.04 (4H, m), 0.66 (4H, m)

[1859] Primer 34: 2-[1-[[4-[3-(ciklobutoksi)fenil]-2,6-difluoro-fenoksi] metil]ciklopropil]sirćetna kiselina [0750][1859] Example 34: 2-[1-[[4-[3-(cyclobutoxy)phenyl]-2,6-difluoro-phenoxy] methyl]cyclopropyl]acetic acid [0750]

[1861] [1861]

[1864] Faza A:2-[1-[[4-[3-(ciklobutoksi)fenil]-2,6-difluoro-fenoksi]metil] ciklopropil]acetonitril[1864] Phase A: 2-[1-[[4-[3-(cyclobutoxy)phenyl]-2,6-difluoro-phenoxy]methyl] cyclopropyl]acetonitrile

[1865] 1-ciklobutoksi-3-jodo-benzen (0.06 g, 0.22 mmol) dobijen u primeru pripreme 60 i 2-[1-[[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]metil]ciklopropil]acetonitril (0.092 g, 0.26 mmol) dobijen u fazi E primera pripreme 30 su rastvoreni u 2 mL 1,2-dimetoksietana i Na<2>CO<3>(2M vodeni rastvor, 0.33 mL, 0.66 mmol), i N<2>gas je dodavan 5 minuta. Dodat je Pd(PPh<3>)<4>(0.025 g, 0.022 mmol), i proizvod je 3 sata mešan na 80°C. Reaktant je dodat vodi i ekstrahovan sa EtOAc. Organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.067 g, 83 %).[1865] 1-cyclobutoxy-3-iodo-benzene (0.06 g, 0.22 mmol) obtained in preparation example 60 and 2-[1-[[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]cyclopropyl]acetonitrile (0.092 g, 0.26 mmol) obtained in phase E of preparation 30 were dissolved in 2 mL of 1,2-dimethoxyethane and Na<2>CO<3> (2M aqueous solution, 0.33 mL, 0.66 mmol), and N<2>gas was added for 5 minutes. Pd(PPh<3>)<4> (0.025 g, 0.022 mmol) was added, and the product was stirred at 80°C for 3 hours. The reactant was added to water and extracted with EtOAc. The organic layer was dried with MgSO4 and purified by column chromatography to give the title compound (0.067 g, 83 %).

[1866] 1H NMR (CDCl<3>) δ 7.31 (1H, t), 7.12 (2H, m), 7.06 (1H, d), 6.94 (1H, m), 6.81 (1H, m), 4.69 (1H, m), 4.03 (2H, s), 2.77 (2H, s), 2.47 (2H, m), 2.20 (2H, m), 1.88 (1H, m), 1.72 (1H, m), 0.74 (4H, m)[1866] 1H NMR (CDCl<3>) δ 7.31 (1H, t), 7.12 (2H, m), 7.06 (1H, d), 6.94 (1H, m), 6.81 (1H, m), 4.69 (1H, m), 4.03 (2H, s), 2.77 (2H, s), 2.47 (2H, m), 2.20 (2H, m), 1.88 (1H, m), 1.72 (1H, m), 0.74 (4H, m)

[1868] Faza B: 2-[1-[[4-[3-(ciklobutoksi)fenil]-2,6-difluoro-fenoksi]metil] ciklopropil]sirćetna kiselina [0753] 2-[1-[[4-[3-(ciklobutoksi)fenil]-2,6-difluoro-fenoksi]metil]ciklopropil]acetonitril (0.067 g, 0.18 mmol) dobijen u fazi A je rastvoren u 2 mL EtOH, i dodat je NaOH (6M vodeni rastvor, 0.18 mL, 1.08 mmol). Proizvod je mešan 16 sati na 100°C. pH je podešena na 3 upotrebom HCl vodenog rastvora, i reaktant je zatim ekstrahovan sa EtOAc. Organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.04 g, 55 %).[1868] Phase B: 2-[1-[[4-[3-(cyclobutoxy)phenyl]-2,6-difluoro-phenoxy]methyl] cyclopropyl]acetic acid [0753] 2-[1-[[4-[3-(cyclobutoxy)phenyl]-2,6-difluoro-phenoxy]methyl]cyclopropyl]acetonitrile (0.067 g, 0.18 mmol) obtained in phase A was dissolved in 2 mL of EtOH. and NaOH (6M aqueous solution, 0.18 mL, 1.08 mmol) was added. The product was mixed for 16 hours at 100°C. The pH was adjusted to 3 using aqueous HCl, and the reactant was then extracted with EtOAc. The organic layer was dried with MgSO4 and purified by column chromatography to give the title compound (0.04 g, 55 %).

[1869] 1H NMR (CDCl<3>) δ 7.29 (1H, t), 7.08 (3H, m), 6.93 (1H, m), 6.80 (1H, m), 4.69 (1H, m), 4.11 (2H, s), 2.65 (2H, s), 2.48 (2H, m), 2.19 (2H, m), 1.88 (1H, m), 1.72 (1H, m), 0.66 (4H, m)[1869] 1H NMR (CDCl<3>) δ 7.29 (1H, t), 7.08 (3H, m), 6.93 (1H, m), 6.80 (1H, m), 4.69 (1H, m), 4.11 (2H, s), 2.65 (2H, s), 2.48 (2H, m), 2.19 (2H, m), 1.88 (1H, m), 1.72 (1H, m), 0.66 (4H, m)

[1870] Primer 35: 4-[[6-[3-(ciklobutoksi)fenil]-3-piridil]oksi]buterna kiselina[1870] Example 35: 4-[[6-[3-(cyclobutoxy)phenyl]-3-pyridyl]oxy]butyric acid

[1871][1871]

[1873] [1873]

[1876] Faza A: etil estar 4-[[6-[3-(ciklobutoksi)fenil]-3-piridil]oksi]buterne kiseline[1876] Phase A: 4-[[6-[3-(cyclobutoxy)phenyl]-3-pyridyl]oxy]butyric acid ethyl ester

[1877] Etil estar 4-[[6-(3-hidroksifenil)-3-piridil]oksi]buterne kiseline (0.061 g, 0.2 mmol) dobijen u fazi B primera pripreme 31 je rastvoren u 2 mL DMF-a i ohlađen do 0°C. Dodat je NaH (60 % u mineralnom ulju, 0.012 g, 0.3 mmol), i proizvod je mešan 1 sat na 0°C. Dodat je bromociklobutan (0.027 g, 0.2 mmol), i proizvod je mešan 6 sati na 70°C. Nakon što je reakcioni rastvor koncentrovan pod smanjenim pritiskom, dodata mu je voda i ekstrahovan je sa EtOAc. Organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.014 g, 19 %).[1877] 4-[[6-(3-Hydroxyphenyl)-3-pyridyl]oxy]butyric acid ethyl ester (0.061 g, 0.2 mmol) obtained in phase B of Preparation Example 31 was dissolved in 2 mL of DMF and cooled to 0°C. NaH (60% in mineral oil, 0.012 g, 0.3 mmol) was added, and the product was stirred for 1 hour at 0°C. Bromocyclobutane (0.027 g, 0.2 mmol) was added, and the product was stirred for 6 hours at 70°C. After the reaction solution was concentrated under reduced pressure, water was added to it, and it was extracted with EtOAc. The organic layer was dried with MgSO4 and purified by column chromatography to give the title compound (0.014 g, 19 %).

[1878] 1H NMR (CDCl<3>) δ 8.35 (1H, m), 7.62 (1H, d), 7.45 (1H, m), 7.41 (1H, m), 7.32 (1H, t), 7.24 (1H, m), 6.83 (1H, m), 4.75 (1H, m), 4.16 (2H, q), 4.10 (2H, t), 2.54 (2H, t), 2.50 (2H, m), 2.17 (4H, m), 1.86 (1H, m), 1.72 (1H, m), 1.27 (3H, t)[1878] 1H NMR (CDCl<3>) δ 8.35 (1H, m), 7.62 (1H, d), 7.45 (1H, m), 7.41 (1H, m), 7.32 (1H, t), 7.24 (1H, m), 6.83 (1H, m), 4.75 (1H, m), 4.16 (2H, q), 4.10 (2H, t), 2.54 (2H, t), 2.50 (2H, m), 2.17 (4H, m), 1.86 (1H, m), 1.72 (1H, m), 1.27 (3H, t)

[1880] Faza B: 4-[[6-[3-(ciklobutoksi)fenil]-3-piridil]oksi]1buterna kiselina[1880] Phase B: 4-[[6-[3-(cyclobutoxy)phenyl]-3-pyridyl]oxy]1-butyric acid

[1881] Etil estar 4-[[6-[3-(ciklobutoksi)fenil]-3-piridil]oksi]buterne kiseline (0.014 g, 0.039 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.013 g, 99 %).[1881] 4-[[6-[3-(cyclobutoxy)phenyl]-3-pyridyl]oxy]butyric acid ethyl ester (0.014 g, 0.039 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.013 g, 99%).

[1882] 1H NMR (CDCl<3>) δ 8.39 (1H, m), 7.62 (1H, d), 7.44 (1H, d), 7.37 (1H, m), 7.32 (1H, t), 7.27 (1H, m), 6.83 (1H, m), 4.74 (1H, m), 4.13 (2H, t), 2.61 (2H, t), 2.48 (2H, m), 2.18 (4H, m), 1.87 (1H, m), 1.70 (1H, m)[1882] 1H NMR (CDCl<3>) δ 8.39 (1H, m), 7.62 (1H, d), 7.44 (1H, d), 7.37 (1H, m), 7.32 (1H, t), 7.27 (1H, m), 6.83 (1H, m), 4.74 (1H, m), 4.13 (2H, t), 2.61 (2H, t), 2.48 (2H, m), 2.18 (4H, m), 1.87 (1H, m), 1.70 (1H, m)

[1884] Primer 36: 4-[[6-[3-(ciklopentoksi)fenil]-3-piridil]oksi]buterna kiselina[1884] Example 36: 4-[[6-[3-(cyclopentoxy)phenyl]-3-pyridyl]oxy]butyric acid

[1885][1885]

[1887] [1887]

[1890] Faza A: etil estar 4-[[6-[3-(ciklopentoksi)fenil]-3-piridil]oksi]buterne kiseline[1890] Phase A: 4-[[6-[3-(cyclopentoxy)phenyl]-3-pyridyl]oxy]butyric acid ethyl ester

[1891] Etil estar 4-[[6-(3-hidroksifenil)-3-piridil]oksi]buterne kiseline (0.068 g, 0.22 mmol) dobijen u fazi B primera pripreme 31 je rastvoren u 2 mL DMF-a i ohlađen do 0°C. Dodat je NaH (60 % u mineralnom ulju, 0.013 g, 0.33 mmol), i proizvod je mešan 1 sat na 0°C. Dodat je bromociklopentan (0.033 g, 0.2 mmol), i proizvod je mešan 16 sati na 70°C. Nakon što je reakcioni rastvor koncentrovan pod smanjenim pritiskom, dodata mu je voda i ekstrahovan je sa EtOAc. Organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.028 g, 34 %).[1891] 4-[[6-(3-Hydroxyphenyl)-3-pyridyl]oxy]butyric acid ethyl ester (0.068 g, 0.22 mmol) obtained in phase B of Preparation Example 31 was dissolved in 2 mL of DMF and cooled to 0°C. NaH (60% in mineral oil, 0.013 g, 0.33 mmol) was added, and the product was stirred for 1 hour at 0°C. Bromocyclopentane (0.033 g, 0.2 mmol) was added, and the product was stirred for 16 hours at 70°C. After the reaction solution was concentrated under reduced pressure, water was added to it, and it was extracted with EtOAc. The organic layer was dried with MgSO4 and purified by column chromatography to give the title compound (0.028 g, 34 %).

[1892] 1H NMR (CDCl<3>) δ 8.35 (1H, m), 7.63 (1H, d), 7.45 (2H, m), 7.32 (1H, t), 7.25 (1H, m), 6.88 (1H, m), 4.87 (1H, m), 4.16 (2H, q), 4.10 (2H, t), 2.54 (2H, t), 2.15 (2H, m), 1.92 (4H, m), 1.82 (2H, m), 1.62 (2H, m), 1.27 (3H, t)[1892] 1H NMR (CDCl<3>) δ 8.35 (1H, m), 7.63 (1H, d), 7.45 (2H, m), 7.32 (1H, t), 7.25 (1H, m), 6.88 (1H, m), 4.87 (1H, m), 4.16 (2H, q), 4.10 (2H, t), 2.54 (2H, t), 2.15 (2H, m), 1.92 (4H, m), 1.82 (2H, m), 1.62 (2H, m), 1.27 (3H, t)

[1894] Faza B: 4-[[6-[3-(ciklopentoksi)fenil]-3-piridil]oksi]buterna kiselina[1894] Phase B: 4-[[6-[3-(cyclopentoxy)phenyl]-3-pyridyl]oxy]butyric acid

[1895] Etil estar 4-[[6-[3-(ciklopentoksi)fenil]-3-piridil]oksi]buterne kiseline (0.028 g, 0.075 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.02 g, 77 %).[1895] 4-[[6-[3-(cyclopentoxy)phenyl]-3-pyridyl]oxy]butyric acid ethyl ester (0.028 g, 0.075 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.02 g, 77%).

[1896] 1H NMR (CDCl<3>+ Metanol-d<4>) δ 8.68 (1H, m), 7.92 (1H, m), 7.83 (1H, m), 7.48 (3H, m), 7.06 (1H, m), 4.99 (1H, m), 4.29 (2H, t), 2.53 (2H, t), 2.19 (2H, m), 2.00 (2H, m), 1.87 (2H, m), 1.80 (2H, m), 1.64 (2H, m)[1896] 1H NMR (CDCl<3>+ Methanol-d<4>) δ 8.68 (1H, m), 7.92 (1H, m), 7.83 (1H, m), 7.48 (3H, m), 7.06 (1H, m), 4.99 (1H, m), 4.29 (2H, t), 2.53 (2H, t), 2.19 (2H, m), 2.00 (2H, m), 1.87 (2H, m), 1.80 (2H, m), 1.64 (2H, m)

[1898] Primer 37: 4-(2'-fenoksi-bifenil-4-iloksi)-buterna kiselina[1898] Example 37: 4-(2'-phenoxy-biphenyl-4-yloxy)-butyric acid

[1899][1899]

[1901] [1901]

[1904] Faza A: etil estar 4-(2'-fenoksi-bifenil-4-iloksi)-buterne kiseline[1904] Phase A: 4-(2'-phenoxy-biphenyl-4-yloxy)-butyric acid ethyl ester

[1905] 2'-fenoksi-bifenil-4-ol (0.022 g, 0.083 mmol), Cs<2>CO<3>(0.055 g, 0.16 mmol) i etil estar 4-bromobuterne kiseline (0.027 g, 0.10 mmol) su rastvoreni u 2 mL DMF-a, i proizvod je mešan na sobnoj temperaturi 2 sata. Čvrsta materija je filtrirana i prečišćena hromatografijom na koloni (eluent:[1905] 2'-phenoxy-biphenyl-4-ol (0.022 g, 0.083 mmol), Cs<2>CO<3> (0.055 g, 0.16 mmol) and 4-bromobutyric acid ethyl ester (0.027 g, 0.10 mmol) were dissolved in 2 mL of DMF, and the product was stirred at room temperature for 2 hours. The solid was filtered and purified by column chromatography (eluent:

[1906] EtOAc/Hex = 1/4) da bi se dobilo naslovno jedinjenje (0.026 g, 86 %).[1906] EtOAc/Hex = 1/4) to give the title compound (0.026 g, 86 %).

[1907] <1>H-NMR (CDCl<3>) δ 7.46(3H, m), 7.26(2H, m), 7.19(1H, m), 7.00(3H, m), 6.89(2H, m), 6.84(2H, m), 4.15 (2H, q), 4.00(2H, t), 2.50(2H, t), 2.10(2H, m), 1.25(3H, t)[1907] <1>H-NMR (CDCl<3>) δ 7.46(3H, m), 7.26(2H, m), 7.19(1H, m), 7.00(3H, m), 6.89(2H, m), 6.84(2H, m), 4.15 (2H, q), 4.00(2H, t), 2.50(2H, t), 2.10(2H, m), 1.25(3H, t)

[1909] Faza B: 4-(2'-fenoksi-bifenil-4-iloksi)-buterna kiselina[1909] Phase B: 4-(2'-phenoxy-biphenyl-4-yloxy)-butyric acid

[1910] Etil estar 4-(2'-fenoksi-bifenil-4-iloksi)-buterne kiseline (26 mg, 0.071 mmol) dobijen u fazi A je rastvoren u svakom 1 mL od IN NaOH, TFH i MeOH, i proizvod je mešan 3 sata na sobnoj temperaturi. Nakon uklanjanja organskog rastvarača, pH je podešena na 3 upotrebom 1N HCl, i proizvod je ekstrahovan sa EtOAc. Organski sloj je osušen bezvodnim sa MgSO<4>i prečišćen hromatografijom na koloni (eluent: EtOAc/Hex = 1/2) da bi se dobilo naslovno jedinjenje (0.018 g, 75 %).[1910] 4-(2'-phenoxy-biphenyl-4-yloxy)-butyric acid ethyl ester (26 mg, 0.071 mmol) obtained in step A was dissolved in 1 mL each of 1N NaOH, TFH, and MeOH, and the product was stirred for 3 hours at room temperature. After removal of the organic solvent, the pH was adjusted to 3 using 1N HCl, and the product was extracted with EtOAc. The organic layer was dried anhydrous with MgSO4 and purified by column chromatography (eluent: EtOAc/Hex = 1/2) to give the title compound (0.018 g, 75 %).

[1911] 1H-NMR (MeOD) δ 7.46(3H, m), 7.31(1H, m), 7.25(3H, m), 7.01(2H, m), 6.89(2H, d), 6.82(2H, d), 4.02(2H, t), 2.48(2H, t), 2.04(2H, m)[1911] 1H-NMR (MeOD) δ 7.46(3H, m), 7.31(1H, m), 7.25(3H, m), 7.01(2H, m), 6.89(2H, d), 6.82(2H, d), 4.02(2H, t), 2.48(2H, t), 2.04(2H, m)

[1913] Primer 38: 4-[4-(2-izopropilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina[1913] Example 38: 4-[4-(2-isopropylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid

[1914][1914]

[1916] [1916]

[1919] Faza A: etil estar 4-[4-(2-izopropilsulfanil-piridin-3-il)-fenoksil-buterne kiseline[1919] Phase A: 4-[4-(2-isopropylsulfanyl-pyridin-3-yl)-phenoxyl-butyric acid ethyl ester

[1920] 4-(2-izopropilsulfanil-piridin-3-il)-fenol (0.015 g, 0.061 mmol) dobijen u primeru pripreme 33, cezijumkarbonat (0.04 g, 0.12 mmol) i etil estar 4-bromobuterne kiseline (0.014 g, 0.07 mmol) su rastvoreni u 2 mL DMF-a, i proizvod je 24 sata mešan na sobnoj temperaturi. Reakcioni rastvor je dodat sa vodenim rastvorom NaCl i ekstrahovan sa EtOAc da bi se izdvojio organski sloj. Organski sloj je osušen bezvodnim MgSO<4>i prečišćena hromatografijom na koloni (eluent: EtOAc/Hex = 1/4) da bi se dobilo naslovno jedinjenje (0.01 g, 45 %).[1920] 4-(2-isopropylsulfanyl-pyridin-3-yl)-phenol (0.015 g, 0.061 mmol) obtained in Preparation Example 33, cesium carbonate (0.04 g, 0.12 mmol) and 4-bromobutyric acid ethyl ester (0.014 g, 0.07 mmol) were dissolved in 2 mL of DMF, and the product was stirred at room temperature for 24 hours. temperature. The reaction solution was added with aqueous NaCl and extracted with EtOAc to separate the organic layer. The organic layer was dried over anhydrous MgSO4 and purified by column chromatography (eluent: EtOAc/Hex = 1/4) to give the title compound (0.01 g, 45 %).

[1921] <1>H-NMR (CDCl<3>) δ 8.41(1H, m), 7.32(3H, m), 7.02(1H, m), 6.94(2H, m), 4.16(2H, q), 4.04(3H, m), 2.53(2H, t), 2.13(2H, m), 1.35(6H, d), 1.27(3H, t)[1921] <1>H-NMR (CDCl<3>) δ 8.41(1H, m), 7.32(3H, m), 7.02(1H, m), 6.94(2H, m), 4.16(2H, q), 4.04(3H, m), 2.53(2H, t), 2.13(2H, m), 1.35(6H, d), 1.27(3H, t)

[1923] Faza B: 4-[4-(2-izopropilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina[1923] Phase B: 4-[4-(2-isopropylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid

[1924] Etil estar 4-[4-(2-izopropilsulfanil-piridin-3-il)-fenoksi]-buterne kiseline (0.01 g, 0.02 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 37 da bi se dobilo naslovno jedinjenje (0.006 g, 65 %).[1924] 4-[4-(2-isopropylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid ethyl ester (0.01 g, 0.02 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 37 to give the title compound (0.006 g, 65%).

[1925] <1>H-NMR (CDCl<3>) δ 8.41(1H, m), 7.32(3H, m), 7.02(1H, m), 6.95(2H, m), 4.06(3H, m), 2.62(2H, t), 2.15(2H, m), 1.35(6H, d)[1925] <1>H-NMR (CDCl<3>) δ 8.41(1H, m), 7.32(3H, m), 7.02(1H, m), 6.95(2H, m), 4.06(3H, m), 2.62(2H, t), 2.15(2H, m), 1.35(6H, d)

[1927] Primer 39: 4-(3,5-difluoro-2'-fenoksi-bifenil-4-iloksi)-buterna kiselina[1927] Example 39: 4-(3,5-difluoro-2'-phenoxy-biphenyl-4-yloxy)-butyric acid

[1928][1928]

[1930] [1930]

[1933] Faza A: etil estar 4-(3,5-difluoro-2'-fenoksi-bifenil-4-iloksi)-buterne kiseline[1933] Phase A: 4-(3,5-difluoro-2'-phenoxy-biphenyl-4-yloxy)-butyric acid ethyl ester

[1934] 3,5-difluoro-2'-fenoksi-bifenil-4-ol (0.017 g, 0.056 mmol) dobijen u primeru pripreme 34 i etil estar 4-bromobuterne kiseline (0.013 g, 0.068 mmol) su korišćeni da bi reagovali na isti način kao u fazi A primera 37 da bi se dobilo naslovno jedinjenje(0.023 g, 95 %).[1934] 3,5-difluoro-2'-phenoxy-biphenyl-4-ol (0.017 g, 0.056 mmol) obtained in Preparative Example 34 and 4-bromobutyric acid ethyl ester (0.013 g, 0.068 mmol) were used to react in the same manner as in Step A of Example 37 to give the title compound (0.023 g, 95%).

[1935] <1>H-NMR (CDCl<3>) δ 7.40(1H, m), 7.30(3H, m), 7.20(1H, m), 7.11(2H, m), 7.05(1H, m), 6.97(1H, m), 6.91(2H, m), 4.15(4H, m), 2.56(2H, t), 2.07(2H, m), 1.27(3H, t)[1935] <1>H-NMR (CDCl<3>) δ 7.40(1H, m), 7.30(3H, m), 7.20(1H, m), 7.11(2H, m), 7.05(1H, m), 6.97(1H, m), 6.91(2H, m), 4.15(4H, m), 2.56(2H, t), 2.07(2H, m), 1.27(3H, t)

[1937] Faza B: 4-(3.5-difluoro-2'-fenoksi-bifenil-4-iloksi)-buterna kiselina[1937] Phase B: 4-(3,5-difluoro-2'-phenoxy-biphenyl-4-yloxy)-butyric acid

[1938] Etil estar 4-(3,5-difluoro-2'-fenoksi-bifenil-4-iloksi)-buterne kiseline (0.022 g, 0.053 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 37 da bi se dobilo naslovno jedinjenje (0.014 g, 69 %).[1938] 4-(3,5-Difluoro-2'-phenoxy-biphenyl-4-yloxy)-butyric acid ethyl ester (0.022 g, 0.053 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 37 to give the title compound (0.014 g, 69%).

[1939] <1>H-NMR (CDCl<3>) δ 7.40(1H, m), 7.30(3H, m), 7.20(1H, m), 7.11(2H, m), 7.05(1H, m), 6.97(1H, m), 6.91(2H, d), 4.19(2H, t), 2.64(2H, t), 2.08(2H, m)[1939] <1>H-NMR (CDCl<3>) δ 7.40(1H, m), 7.30(3H, m), 7.20(1H, m), 7.11(2H, m), 7.05(1H, m), 6.97(1H, m), 6.91(2H, d), 4.19(2H, t), 2.64(2H, t), 2.08(2H, m)

[1941] Primer 40: 4-[4-(2-ciklopentilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina[1941] Example 40: 4-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid

[1942][1942]

[1944] [1944]

[1947] Faza A: etil estar 4-[4-(2-ciklopentilsulfanil-piridin-3-il)-fenoksi]-buterne kiseline[1947] Phase A: 4-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid ethyl ester

[1948] 4-(2-ciklopentilsulfanil-piridin-3-il)-fenol (0.024 g, 0.088 mmol) dobijen u primeru pripreme 35 je korišćen da bi reagovao na isti način kao u fazi A primera 38 da bi se dobilo naslovno jedinjenje (0.03 g, 88 %).[1948] 4-(2-Cyclopentylsulfanyl-pyridin-3-yl)-phenol (0.024 g, 0.088 mmol) obtained in Preparative Example 35 was used to react in the same manner as in Step A of Example 38 to give the title compound (0.03 g, 88 %).

[1949] <1>H-NMR (CDCl<3>) δ 8.38(1H, m), 7.32(3H, m), 7.01(1H, m), 6.94(2H, m), 4.14(2H, q), 4.05(3H, m), 2.52(2H, t), 2.13(4H, m), 1.60(2H, m), 1.66(4H, m), 1.26(3H, t)[1949] <1>H-NMR (CDCl<3>) δ 8.38(1H, m), 7.32(3H, m), 7.01(1H, m), 6.94(2H, m), 4.14(2H, q), 4.05(3H, m), 2.52(2H, t), 2.13(4H, m), 1.60(2H, m), 1.66(4H, m), 1.26(3H, t)

[1951] Faza B: 4-[4-(2-ciklopentilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina[1951] Phase B: 4-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid

[1952] Etil estar 4-[4-(2-ciklopentilsulfanil-piridin-3-il)-fenoksi]-buterne kiseline (0.03 g, 0.077 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 37 da bi se dobilo naslovno jedinjenje (0.017 g, 63 %).[1952] 4-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid ethyl ester (0.03 g, 0.077 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 37 to give the title compound (0.017 g, 63%).

[1953] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.32(3H, m), 7.01(1H, m), 6.95(2H, m), 4.07(3H, m), 2.62(2H, t), 2.15(4H, m), 1.69(2H, m), 1.58(4H, m)[1953] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.32(3H, m), 7.01(1H, m), 6.95(2H, m), 4.07(3H, m), 2.62(2H, t), 2.15(4H, m), 1.69(2H, m), 1.58(4H, m)

[1954] Primer 41: 4-[2,6-difluoro-4-(2-izopropilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina[1954] Example 41: 4-[2,6-difluoro-4-(2-isopropylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid

[1955][1955]

[1957] [1957]

[1960] 2,6-difluoro-4-(2-izopropilsulfanil-piridin-3-il)-fenol (0.015 g, 0.053 mmol) dobijen u primeru pripreme 63 je korišćen da bi reagovao na isti način kao u fazama A i B primera 38 da bi se dobilo naslovno jedinjenje (0.005 g, 27 %).[1960] 2,6-Difluoro-4-(2-isopropylsulfanyl-pyridin-3-yl)-phenol (0.015 g, 0.053 mmol) obtained in Preparative Example 63 was used to react in the same manner as steps A and B of Example 38 to give the title compound (0.005 g, 27%).

[1961] <1>H-NMR (CDCl<3>) δ 8.44(1H, m), 7.32(1H, m), 7.03(1H, m), 6.99(2H, m), 4.25(2H, t), 4.06(1H, m), 2.67(2H, t), 2.13(2H, m), 1.37(6H, d)[1961] <1>H-NMR (CDCl<3>) δ 8.44(1H, m), 7.32(1H, m), 7.03(1H, m), 6.99(2H, m), 4.25(2H, t), 4.06(1H, m), 2.67(2H, t), 2.13(2H, m), 1.37(6H, d)

[1963] Primer 42: 4-[2,6-difluoro-4-(2-fenoksi-piridin-3-il)-fenoksi]-buterna kiselina[1963] Example 42: 4-[2,6-difluoro-4-(2-phenoxy-pyridin-3-yl)-phenoxy]-butyric acid

[1964][1964]

[1966] [1966]

[1969] 3-jodo-2-fenoksi-piridin (0.043 g, 0.144 mmol) dobijen u primeru pripreme 36 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.048 g, 0.131 mmol) dobijen u primeru pripreme 2 su korišćeni da bi sekvencijalno reagovali na isti način kao u fazi B primera pripreme 33 i fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.004 g, 7 %).[1969] 3-iodo-2-phenoxy-pyridine (0.043 g, 0.144 mmol) obtained in Preparation Example 36 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.048 g, 0.131 mmol) obtained in Preparation Example 2 were used to would react sequentially in the same manner as in Phase B of Preparation Example 33 and Phase B of Example 1 to give the title compound (0.004 g, 7 %).

[1970] <1>H-NMR (CDCl<3>) δ 8.42(1H, m), 7.12(1H, m), 7.40(2H, m), 7.22(3H, m), 7.11(3H, m), 4.23(2H, t), 2.65(2H, t), 2.11(2H, m)[1970] <1>H-NMR (CDCl<3>) δ 8.42(1H, m), 7.12(1H, m), 7.40(2H, m), 7.22(3H, m), 7.11(3H, m), 4.23(2H, t), 2.65(2H, t), 2.11(2H, m)

[1972] Primer 43: 4-[2,6-difluoro-4-(2-izopropoksi-piridin-3-il)-fenoksi]-buterna kiselina[1972] Example 43: 4-[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenoxy]-butyric acid

[1973][1973]

[1975] [1975]

[1978] 3-jodo-2-izopropoksi-piridin (0.029 g, 0.11 mmol) dobijen u primeru pripreme 37 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.034 g, 0.091 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.011 g, 21 %).[1978] 3-iodo-2-isopropoxy-pyridine (0.029 g, 0.11 mmol) obtained in Preparation Example 37 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.034 g, 0.091 mmol) obtained in Preparation Example 2 were used to would react in the same way as in steps A and B of Example 1 to give the title compound (0.011 g, 21 %).

[1979] <1>H-NMR (CDCl<3>) δ 8.14(1H, m), 7.55(1H, m), 7.15(2H, m), 6.91(1H, m), 5.41(1H, m), 4.24(2H, t), 2.67(2H, t), 2.13(2H, m), 1.37(6H, d)[1979] <1>H-NMR (CDCl<3>) δ 8.14(1H, m), 7.55(1H, m), 7.15(2H, m), 6.91(1H, m), 5.41(1H, m), 4.24(2H, t), 2.67(2H, t), 2.13(2H, m), 1.37(6H, d)

[1981] Primer 44: 4-[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina[1981] Example 44: 4-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid

[1982][1982]

[1984] [1984]

[1987] 2-ciklopentoksi-3-jodo-piridin (0.042 g, 0.14 mmol) dobijen u primeru pripreme 38 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.045 g, 0.121 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.021 g, 41 %).[1987] 2-Cyclopentoxy-3-iodo-pyridine (0.042 g, 0.14 mmol) obtained in Preparation Example 38 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.045 g, 0.121 mmol) obtained in Preparation Example 2 were used to would react in the same way as in steps A and B of Example 1 to give the title compound (0.021 g, 41 %).

[1988] <1>H-NMR (CDCl<3>) δ 8.14(1H, m), 7.55(1H, m), 7.15(2H, m), 6.91(1H, m), 5.52(1H, m), 4.24(2H, t), 2.67(2H, t), 2.13(2H, m), 1.95(2H, m), 1.78(4H, m), 1.65(2H, m)[1988] <1>H-NMR (CDCl<3>) δ 8.14(1H, m), 7.55(1H, m), 7.15(2H, m), 6.91(1H, m), 5.52(1H, m), 4.24(2H, t), 2.67(2H, t), 2.13(2H, m), 1.95(2H, m), 1.78(4H, m), 1.65(2H, m)

[1990] Primer 45: 4-[4-(2-ciklopentilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina[1990] Example 45: 4-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid

[1991][1991]

[1993] [1993]

[1996] 2-ciklopentilsulfanil-3-jodo-piridin (0.026 g, 0.09 mmol) dobijen u primeru pripreme 39 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.031 g, 0.083 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.009 g, 25 %).[1996] 2-cyclopentylsulfanyl-3-iodo-pyridine (0.026 g, 0.09 mmol) obtained in preparation example 39 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.031 g, 0.083 mmol) obtained in preparation example 2 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.009 g, 25 %).

[1997] <1>H-NMR (CDCl<3>) δ 8.42(1H, m), 7.30(1H, m), 7.02(3H, m), 4.25(2H, t), 4.07(1H, m), 2.67(2H, t), 2.15(4H, m), 1.69(2H, m), 1.58(4H, m)[1997] <1>H-NMR (CDCl<3>) δ 8.42(1H, m), 7.30(1H, m), 7.02(3H, m), 4.25(2H, t), 4.07(1H, m), 2.67(2H, t), 2.15(4H, m), 1.69(2H, m), 1.58(4H, m)

[1999] Primer 46: 4- [4-(2-ciklopropilmetoksi-piridin-3-il)-2,6-difluoro-fenoksi] -buterna kiselina[1999] Example 46: 4-[4-(2-cyclopropylmethoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid

[2000][2000]

[2002] [2002]

[2003] 2-ciklopropilmetoksi-3-jodo-piridin (0.05 g, 0.181 mmol) dobijen u primeru pripreme 40 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.061 g, 0.165 mmol) dobijen u fazi C primera pripreme 2 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.022 g, 34 %).[2003] 2-cyclopropylmethoxy-3-iodo-pyridine (0.05 g, 0.181 mmol) obtained in preparation example 40 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.061 g, 0.165 mmol) obtained in phase C of preparation example 2 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.022 g, 34 %).

[2004] <1>H-NMR (CDCl<3>) δ 8.12(1H, m), 7.57(1H, m), 7.20(2H, m), 6.94(1H, m), 4.23(4H, m), 2.67(2H, t), 2.12 (2H, m), 1.42(1H, m), 0.59(2H, m), 0.34(2H, m)[2004] <1>H-NMR (CDCl<3>) δ 8.12(1H, m), 7.57(1H, m), 7.20(2H, m), 6.94(1H, m), 4.23(4H, m), 2.67(2H, t), 2.12 (2H, m), 1.42(1H, m), 0.59(2H, m), 0.34(2H, m)

[2006] Primer 47: 4-[4-(2-ciklopropilmetilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina [0803][2006] Example 47: 4-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid [0803]

[2008] [2008]

[2011] 2-ciklopropilmetilsulfanil-3-(3,5-difluoro-4-metoksi-fenil)-piridin (0.033 g, 0.107 mmol) dobijen u primeru pripreme 41 je korišćen da bi reagovao sekvencijalno na isti način kao u fazi C primera pripreme 33, fazi A primera 38 i fazi B primera 37 da bi se dobilo naslovno jedinjenje (0.0088 g, 13 %).[2011] 2-Cyclopropylmethylsulfanyl-3-(3,5-difluoro-4-methoxy-phenyl)-pyridine (0.033 g, 0.107 mmol) obtained in Preparative Example 41 was used to react sequentially in the same manner as in Step C of Preparative Example 33, Step A of Example 38 and Step B of Example 37 to give the title compound (0.0088 g, 13%).

[2012] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.31(1H, m), 7.02(3H, m), 4.26(2H, m), 3.11(2H, m), 2.69 (2H, m), 2.15(2H, m), 1.15(1H, m), 0.57(2H, m), 0.34(2H, m)[2012] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.31(1H, m), 7.02(3H, m), 4.26(2H, m), 3.11(2H, m), 2.69 (2H, m), 2.15(2H, m), 1.15(1H, m), 0.57(2H, m), 0.34(2H, m)

[2014] Primer 48: 4-[4-(2-ciklobutilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina[2014] Example 48: 4-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid

[2015][2015]

[2017] [2017]

[2020] 2-ciklobutilsulfanil-3-(4-metoksi-fenil)-piridin (0.009 g, 0.034 mmol) dobijen u primeru pripreme 42 je korišćen da bi reagovao sekvencijalno na isti način kao u fazi C primera pripreme 33, fazi A primera 38 i fazi B primera 37 da bi se dobilo naslovno jedinjenje (0.0034 g, 28%).[2020] 2-Cyclobutylsulfanyl-3-(4-methoxy-phenyl)-pyridine (0.009 g, 0.034 mmol) obtained in Preparative Example 42 was used to react sequentially in the same manner as in Step C of Preparative Example 33, Step A of Example 38, and Step B of Example 37 to give the title compound (0.0034 g, 28%).

[2021] <1>H-NMR (CDCl<3>) δ 8.38(1H, m), 7.34(3H, m), 7.02(3H, m), 4.42(1H, m), 4.08(2H, m), 2.62 (2H, m), 2.49(2H, m), 2.16(2H, m), 2.01(4H, m)[2021] <1>H-NMR (CDCl<3>) δ 8.38(1H, m), 7.34(3H, m), 7.02(3H, m), 4.42(1H, m), 4.08(2H, m), 2.62 (2H, m), 2.49(2H, m), 2.16(2H, m), 2.01(4H, m)

[2022] Primer 49: 4-[4-(2-ciklopropilmetilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina[2022] Example 49: 4-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid

[2023][2023]

[2025] [2025]

[2028] 2-ciklopropilmetilsulfanil-3-(4-metoksi-fenil)-piridin (0.02 g, 0.073 mmol) dobijen u primeru pripreme 43 je korišćen da bi reagovao sekvencijalno na isti način kao u fazi C primera pripreme 33, fazi A primera 38 i fazi B primera 37 da bi se dobilo naslovno jedinjenje (0.0031 g, 12%).[2028] 2-cyclopropylmethylsulfanyl-3-(4-methoxy-phenyl)-pyridine (0.02 g, 0.073 mmol) obtained in Preparative Example 43 was used to react sequentially in the same manner as in Step C of Preparative Example 33, Step A of Example 38 and Step B of Example 37 to give the title compound (0.0031 g, 12%).

[2029] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.37(3H, m), 7.02(3H, m), 4.09(2H, m), 3.09(2H, m), 2.63 (2H, m), 2.13(2H, m), 1.09(1H, m), 0.54(2H, m), 0.27(2H, m)[2029] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.37(3H, m), 7.02(3H, m), 4.09(2H, m), 3.09(2H, m), 2.63 (2H, m), 2.13(2H, m), 1.09(1H, m), 0.54(2H, m), 0.27(2H, m)

[2031] Primer 50: 4-[4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina[2031] Example 50: 4-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid

[2032][2032]

[2034] [2034]

[2037] Faza A: etil estar 4-[4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina [0813] 2-ciklobutilsulfanil-3-jodo-piridin (0.15 g, 0.394 mmol) dobijen u primeru pripreme 44 i etil estar etil 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.12 g, 0.329 mmol) dobijen u primeru pripreme 2 su rastvoreni u 1 mL 2M Na<2>CO<3>vodenog rastvora i 2 mL 1,2-dimetoksietana, i N<2>gas je dodavan 5 minuta. Dodat je PdCl<2>(PPh<3>)<2>(0.012 g, 0.016 mmol) i proizvod je mešan pod refluksom 5 sati. Nakon završetka reakcije, proizvod je razblažen vodom i ekstrahovan sa EtOAc. Organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni (eluent: EtOAc/ Hex = 1/4) da bi se dobilo naslovno jedinjenje (0.084 g, 62 %).[2037] Phase A: 4-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid ethyl ester [0813] 2-cyclobutylsulfanyl-3-iodo-pyridine (0.15 g, 0.394 mmol) obtained in Preparation Example 44 and ethyl ester 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid (0.12 g, 0.329 mmol) obtained in Preparation Example 2 was dissolved in 1 mL of 2M Na<2>CO<3>aqueous solution and 2 mL of 1,2-dimethoxyethane, and N<2>gas was added for 5 minutes. PdCl<2>(PPh<3>)<2> (0.012 g, 0.016 mmol) was added and the product was stirred under reflux for 5 hours. After completion of the reaction, the product was diluted with water and extracted with EtOAc. The organic layer was dried with MgSO4 and purified by column chromatography (eluent: EtOAc/Hex = 1/4) to give the title compound (0.084 g, 62 %).

[2038] <1>H-NMR (CDCl<3>) δ 8.41(1H, m), 7.32(1H, m), 7.01(3H, m), 4.42(1H, m), 4.24(2H, m), 4.16(2H, q), 2.59(2H, m), 2.69(2H, m), 2.13(3H, m), 2.06(3H, m), 1.28(3H, t)[2038] <1>H-NMR (CDCl<3>) δ 8.41(1H, m), 7.32(1H, m), 7.01(3H, m), 4.42(1H, m), 4.24(2H, m), 4.16(2H, q), 2.59(2H, m), 2.69(2H, m), 2.13(3H, m), 2.06(3H, m), 1.28(3H, t)

[2040] Faza B: 4-[4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina[2040] Phase B: 4-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid

[2041] Etil estar 4-[4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterne kiseline (0.068 g, 0.166 mmol) dobijen u fazi A je izreagovan na isti način kao u fazi B primera 37 da bi se dobilo naslovno jedinjenje (0.031 g, 50 %).[2041] 4-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid ethyl ester (0.068 g, 0.166 mmol) obtained in step A was reacted in the same manner as in step B of Example 37 to give the title compound (0.031 g, 50%).

[2042] <1>H-NMR (CDCl<3>) δ 8.41(1H, m), 7.32(1H, m), 7.01(3H, m), 4.41(1H, m), 4.26(2H, m), 2.69(2H, m), 2.51(2H, m), 2.15(3H, m), 2.06(3H, m)[2042] <1>H-NMR (CDCl<3>) δ 8.41(1H, m), 7.32(1H, m), 7.01(3H, m), 4.41(1H, m), 4.26(2H, m), 2.69(2H, m), 2.51(2H, m), 2.15(3H, m), 2.06(3H, m)

[2043] Primer 51: 4-[4-(2-propilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina[2043] Example 51: 4-[4-(2-propylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid

[2044][2044]

[2046] [2046]

[2049] 3-(4-metoksi-fenil)-2-propilsulfanil-piridin (0.023 g, 0.088 mmol) dobijen u primeru pripreme 45 je korišćen da bi reagovao sekvencijalno na isti način kao u fazi C primera pripreme 33, fazi A primera 38 i fazi B primera 37 da bi se dobilo naslovno jedinjenje (0.005 g, 18 %).[2049] 3-(4-Methoxy-phenyl)-2-propylsulfanyl-pyridine (0.023 g, 0.088 mmol) obtained in Preparative Example 45 was used to react sequentially in the same manner as in Phase C of Preparative Example 33, Phase A of Example 38 and Phase B of Example 37 to give the title compound (0.005 g, 18%).

[2050] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.34(3H, m), 7.02(1H, m), 6.95(2H, m), 4.08(2H, m), 3.12(2H, m), 2.62 (2H, m), 2.16(2H, m), 1.70(2H, m), 1.00(3H, t)[2050] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.34(3H, m), 7.02(1H, m), 6.95(2H, m), 4.08(2H, m), 3.12(2H, m), 2.62 (2H, m), 2.16(2H, m), 1.70(2H, m), 1.00(3H, t)

[2052] Primer 52: 4-(3,5-difluoro-2'-izopropoksi-bifenil-4-iloksi)-buterna kiselina[2052] Example 52: 4-(3,5-difluoro-2'-isopropoxy-biphenyl-4-yloxy)-butyric acid

[2053][2053]

[2055] [2055]

[2058] 1-bromo-2-izopropoksi-benzen (0.051 g, 0.237 mmol) dobijen u primeru pripreme 46 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.067 g, 0.182 mmol) dobijen u primeru pripreme 2 su korišćeni da bi sekvencijalno reagovali na isti način kao u fazi A primera 50 i fazi B primera 37 da bi se dobilo naslovno jedinjenje (0.022 g, 35 %).[2058] 1-Bromo-2-isopropoxy-benzene (0.051 g, 0.237 mmol) obtained in Preparation Example 46 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.067 g, 0.182 mmol) obtained in Preparation Example 2 were used to reacted sequentially in the same manner as in Phase A of Example 50 and Phase B of Example 37 to give the title compound (0.022 g, 35 %).

[2059] <1>H-NMR (CDCl<3>) δ 7.28(2H, m), 7.14(2H, m), 6.98(2H, m), 4.49(1H, m), 4.23(2H, t), 2.69 (2H, m), 2.12(2H, m), 1.29(6H, d)[2059] <1>H-NMR (CDCl<3>) δ 7.28(2H, m), 7.14(2H, m), 6.98(2H, m), 4.49(1H, m), 4.23(2H, t), 2.69 (2H, m), 2.12(2H, m), 1.29(6H, d)

[2061] Primer 53: 4-(2'-ciklobutoksi-3,5-difluoro-bifenil-4-iloksi)-buterna kiselina[2061] Example 53: 4-(2'-cyclobutoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric acid

[2062][2062]

[2064] [2064]

[2067] 1-bromo-2-ciklobutoksi-benzen (0.023 g, 0.101 mmol) dobijen u primeru pripreme 47 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.029 g, 0.0779 mmol) dobijen u primeru pripreme 2 su korišćeni da bi sekvencijalno reagovali na isti način kao u fazi A primera 50 i fazi B primera 37 da bi se dobilo naslovno jedinjenje (0.01 g, 35 %).[2067] 1-Bromo-2-cyclobutoxy-benzene (0.023 g, 0.101 mmol) obtained in Preparation Example 47 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.029 g, 0.0779 mmol) obtained in Preparation Example 2 were used to would be sequentially reacted in the same manner as in phase A of example 50 and phase B of example 37 to give the title compound (0.01 g, 35 %).

[2068] <1>H-NMR (CDCl<3>) δ 7.28(2H, m), 7.15(2H, m), 6.99(1H, m), 6.80(1H, m), 4.65(1H, m), 4.23(2H, m), 2.68 (2H, m), 2.44(2H, m), 2.17(4H, m), 1.85(1H, m), 1.70(1H, m)[2068] <1>H-NMR (CDCl<3>) δ 7.28(2H, m), 7.15(2H, m), 6.99(1H, m), 6.80(1H, m), 4.65(1H, m), 4.23(2H, m), 2.68 (2H, m), 2.44(2H, m), 2.17(4H, m), 1.85(1H, m), 1.70(1H, m)

[2070] Primer 54: 4-(2'-ciklopropilmetoksi-3,5-difluoro-bifenil-4-iloksi)-buterna kiselina[2070] Example 54: 4-(2'-cyclopropylmethoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric acid

[2071][2071]

[2073] [2073]

[2076] 1-bromo-2-ciklopropilmetoksi-benzen (0.054 g, 0.23 mmol) dobijen u primeru pripreme 48 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.067 g, 0.182 mmol) dobijen u primeru pripreme 2 je korišćen da bi reagovao sekvencijalno na isti način kao u fazi A primera 50 i fazi B primera 37 da bi se dobilo naslovno jedinjenje (0.021 g, 32 %).[2076] 1-Bromo-2-cyclopropylmethoxy-benzene (0.054 g, 0.23 mmol) obtained in Preparation Example 48 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.067 g, 0.182 mmol) obtained in Preparation Example 2 were used to prepare reacted sequentially in the same manner as in Phase A of Example 50 and Phase B of Example 37 to give the title compound (0.021 g, 32 %).

[2077] <1>H-NMR (CDCl<3>) δ 7.29(2H, m), 7.16(2H, m), 6.99(1H, m), 6.94(1H, m), 4.23(2H, m), 3.83(2H, m), 2.69(2H, m), 2.13(2H, m), 1.22(1H, m), 0.61(2H, m), 0.31(2H, m)[2077] <1>H-NMR (CDCl<3>) δ 7.29(2H, m), 7.16(2H, m), 6.99(1H, m), 6.94(1H, m), 4.23(2H, m), 3.83(2H, m), 2.69(2H, m), 2.13(2H, m), 1.22(1H, m), 0.61(2H, m), 0.31(2H, m)

[2079] Primer 55: 4-(2'-ciklopentiloksi-3,5-difluoro-bifenil-4-iloksi)-buterna kiselina[2079] Example 55: 4-(2'-cyclopentyloxy-3,5-difluoro-biphenyl-4-yloxy)-butyric acid

[2080][2080]

[2082] [2082]

[2085] 1-bromo-2-ciklopentoksi-benzen (0.079 g, 0.33 mmol) dobijen u primeru pripreme 49 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.093 g, 0.25 mmol) dobijen u primeru pripreme 2 su korišćeni da bi sekvencijalno reagovali na isti način kao u fazi A primera 50 i fazi B primera 37 da bi se dobilo naslovno jedinjenje (0.047 g, 50 %).[2085] 1-Bromo-2-cyclopentoxy-benzene (0.079 g, 0.33 mmol) obtained in Preparation Example 49 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.093 g, 0.25 mmol) obtained in Preparation Example 2 were used to prepare reacted sequentially in the same manner as in Phase A of Example 50 and Phase B of Example 37 to give the title compound (0.047 g, 50 %).

[2086] <1>H-NMR (CDCl<3>) δ 7.28(2H, m), 7.13(2H, m), 6.96(2H, m), 4.77(1H, m), 4.23(2H, m), 2.68(2H, t), 2.12(2H, m), 1.86(4H, m), 1.64(2H, m), 1.55(2H, m)[2086] <1>H-NMR (CDCl<3>) δ 7.28(2H, m), 7.13(2H, m), 6.96(2H, m), 4.77(1H, m), 4.23(2H, m), 2.68(2H, t), 2.12(2H, m), 1.86(4H, m), 1.64(2H, m), 1.55(2H, m)

[2088] Primer 56: 4-(2'-ciklopentiloksi-bifenil-4-iloksi)-buterna kiselina[2088] Example 56: 4-(2'-cyclopentyloxy-biphenyl-4-yloxy)-butyric acid

[2089][2089]

[2091] [2091]

[2092] 1-bromo-2-ciklopentoksi-benzen (0.063 g, 0.26 mmol) dobijen u primeru pripreme 49 i etil estar 4-[4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.067 g, 0.20 mmol) dobijen u primeru pripreme 1 su korišćeni da bi sekvencijalno reagovali na isti način kao u fazi A primera 50 i fazi B primera 37 da bi se dobilo naslovno jedinjenje (0.027 g, 39 %).[2092] 1-Bromo-2-cyclopentoxy-benzene (0.063 g, 0.26 mmol) obtained in Preparation Example 49 and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.067 g, 0.20 mmol) obtained in Preparation Example 1 were used to react sequentially in the same manner. as in Phase A of Example 50 and Phase B of Example 37 to give the title compound (0.027 g, 39 %).

[2093] <1>H-NMR (CDCl<3>) δ 7.46(2H, m), 7.28(2H, m), 6.97(2H, m), 6.89(2H, m), 4.74(1H, m), 4.07(2H, m), 2.62(2H, t), 2.15(2H, m), 1.82(4H, m), 1.64(2H, m), 1.55(2H, m)[2093] <1>H-NMR (CDCl<3>) δ 7.46(2H, m), 7.28(2H, m), 6.97(2H, m), 6.89(2H, m), 4.74(1H, m), 4.07(2H, m), 2.62(2H, t), 2.15(2H, m), 1.82(4H, m), 1.64(2H, m), 1.55(2H, m)

[2095] Primer 57: 4-(2'-izopropoksi-bifenil-4-iloksi)-buterna kiselina[2095] Example 57: 4-(2'-isopropoxy-biphenyl-4-yloxy)-butyric acid

[2096][2096]

[2098] [2098]

[2101] 1-bromo-2-izopropoksi-benzen (0.058 g, 0.26 mmol) dobijen u primeru pripreme 46 i etil estar 4-[4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksilbuterne kiseline (0.069 g, 0.20 mmol) dobijen u primeru pripreme 1 su korišćeni da bi sekvencijalno reagovali na isti način kao u fazi A primera 50 i fazi B primera 37 da bi se dobilo naslovno jedinjenje (0.026 g, 40 %).[2101] 1-Bromo-2-isopropoxy-benzene (0.058 g, 0.26 mmol) obtained in Preparation Example 46 and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxybutyric acid ethyl ester (0.069 g, 0.20 mmol) obtained in Preparation Example 1 were used to react sequentially in the same manner as in Phase A of Example 50 and Phase B of Example 37 to give the title compound (0.026 g, 40 %).

[2102] <1>H-NMR (CDCl<3>) δ 7.48(2H, m), 7.28(2H, m), 6.96(2H, m), 6.90(2H, m), 4.41(1H, m), 4.06(2H, m), 2.61(2H, t), 2.14(2H, m), 1.24(6H, d)[2102] <1>H-NMR (CDCl<3>) δ 7.48(2H, m), 7.28(2H, m), 6.96(2H, m), 6.90(2H, m), 4.41(1H, m), 4.06(2H, m), 2.61(2H, t), 2.14(2H, m), 1.24(6H, d)

[2104] Primer 58: 4-(2'-ciklopropilmetoksi-bifenil-4-iloksi)-buterna kiselina[2104] Example 58: 4-(2'-cyclopropylmethoxy-biphenyl-4-yloxy)-butyric acid

[2105][2105]

[2107] [2107]

[2110] 1-bromo-2-ciklopropilmetoksi-benzen (0.059 g, 0.26 mmol) dobijen u primeru pripreme 48 i etil estar 4-[4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksilbuterne kiseline (0.066 g, 0.19 mmol) dobijen u primeru pripreme 1 su korišćeni da bi sekvencijalno reagovali na isti način kao u fazi A primera 50 i fazi B primera 37 da bi se dobilo naslovno jedinjenje (0.024 g, 36 %).[2110] 1-Bromo-2-cyclopropylmethoxy-benzene (0.059 g, 0.26 mmol) obtained in Preparation Example 48 and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxybutyric acid ethyl ester (0.066 g, 0.19 mmol) obtained in Preparation Example 1 were used to react sequentially in the same manner. as in Phase A of Example 50 and Phase B of Example 37 to give the title compound (0.024 g, 36 %).

[2111] <1>H-NMR (CDCl<3>) δ 7.51(2H, m), 7.29(2H, m), 6.99(2H, m), 6.92(2H, m), 4.06(2H, m), 3.79(2H, d), 2.61(2H, t), 2.14(2H, m), 1.19(1H, m), 0.55(2H, m), 0.26(2H, m)[2111] <1>H-NMR (CDCl<3>) δ 7.51(2H, m), 7.29(2H, m), 6.99(2H, m), 6.92(2H, m), 4.06(2H, m), 3.79(2H, d), 2.61(2H, t), 2.14(2H, m), 1.19(1H, m), 0.55(2H, m), 0.26(2H, m)

[2112] Primer 59: 4-[4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-2-metil-buterna kiselina [0841][2112] Example 59: 4-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-2-methyl-butyric acid [0841]

[2114] [2114]

[2117] 4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-difluoro-fenol (0.078 g, 0.26 mmol) dobijen u primeru pripreme 51 i etil estar 4-bromo-2-metil-buterne kiseline (0.055 g, 0.266 mmol) dobijen u primeru pripreme 50 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 37 da bi se dobilo naslovno jedinjenje (0.043 g, 40 %).[2117] 4-(2-Cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenol (0.078 g, 0.26 mmol) obtained in Preparation Example 51 and 4-bromo-2-methyl-butyric acid ethyl ester (0.055 g, 0.266 mmol) obtained in Preparation Example 50 were used to react in the same way as in steps A and B of Example 37 to give the title compound (0.043 g, 40 %).

[2118] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.30(1H, m), 6.98(3H, m), 4.41(1H, m), 4.26(2H, m), 2.89(1H, m), 2.50(2H, m), 2.25(1H, m), 2.02(4H, m), 1.90(1H, m), 1.31(3H, d)[2118] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.30(1H, m), 6.98(3H, m), 4.41(1H, m), 4.26(2H, m), 2.89(1H, m), 2.50(2H, m), 2.25(1H, m), 2.02(4H, m), 1.90(1H, m), 1.31(3H, d)

[2120] Primer 60: 2-[4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-difluoro-fenoksimetil]-ciklopropan ekarboksilna kiselina[2120] Example 60: 2-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxymethyl]-cyclopropane carboxylic acid

[2121][2121]

[2123] [2123]

[2126] 2-ciklobutilsulfanil-3-jodo-piridin (0.035 g, 0.12 mmol) dobijen u primeru pripreme 44 i etil estar 2-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenoksimetil]-ciklopropankarboksilne kiseline (0.042 g, 0.112 mmol) dobijen u fazi D primera pripreme 52 su korišćeni da bi sekvencijalno reagovali na isti način kao u fazi A primera 50 i fazi B primera 37 da bi se dobilo naslovno jedinjenje (0.013 g, 27 %).[2126] 2-cyclobutylsulfanyl-3-iodo-pyridine (0.035 g, 0.12 mmol) obtained in preparation example 44 and 2-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-cyclopropanecarboxylic acid ethyl ester (0.042 g, 0.112 mmol) obtained in phase D of Preparation Example 52 was used to react sequentially in the same manner as in Phase A of Example 50 and Phase B of Example 37 to give the title compound (0.013 g, 27 %).

[2127] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.32(1H, m), 7.00(3H, m), 4.40(1H, m), 4.16(1H, m), 4.05(1H, m), 2.50(2H, m), 2.03(5H, m), 1.72(1H, m), 1.35(1H, m), 1.06(1H, m)[2127] <1>H-NMR (CDCl<3>) δ 8.40(1H, m), 7.32(1H, m), 7.00(3H, m), 4.40(1H, m), 4.16(1H, m), 4.05(1H, m), 2.50(2H, m), 2.03(5H, m), 1.72(1H, m), 1.35(1H, m), 1.06(1H, m)

[2129] Primer 61: 4-[4-(2-ciklobutilsulfanil-piridin-3-il)-2,5-difluoro-fenoksi]-buterna kiselina[2129] Example 61: 4-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,5-difluoro-phenoxy]-butyric acid

[2130][2130]

[2132] [2132]

[2135] 2-ciklobutilsulfanil-3-jodo-piridin (0.11 g, 0.38 mmol) dobijen u primeru pripreme 44 i etil estar 4[2135] 2-cyclobutylsulfanyl-3-iodo-pyridine (0.11 g, 0.38 mmol) obtained in preparation example 44 and ethyl ester 4

[2136] [2,5-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenoksi]-buterne kiseline (0.132 g, 0.35 mmol) dobijen u fazi C primera pripreme 53 su korišćeni da bi sekvencijalno reagovali na isti način kao u fazi A primera 50 i fazi B primera 37 da bi se dobilo naslovno jedinjenje (0.061 g, 44 %).[2136] [2,5-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-butyric acid (0.132 g, 0.35 mmol) obtained in Step C of Preparation Example 53 was used to react sequentially in the same manner as in Step A of Example 50 and Step B of Example 37 to give the title compound (0.061 g, 44 %).

[2137] <1>H-NMR (CDCl<3>) δ 8.41(1H, m), 7.35(1H, m), 7.00(2H, m), 6.78(1H, m), 4.41(1H, m), 4.11(2H, m), 2.64(2H, m), 2.48(2H, m), 2.19(2H, m), 2.02(4H, m)[2137] <1>H-NMR (CDCl<3>) δ 8.41(1H, m), 7.35(1H, m), 7.00(2H, m), 6.78(1H, m), 4.41(1H, m), 4.11(2H, m), 2.64(2H, m), 2.48(2H, m), 2.19(2H, m), 2.02(4H, m)

[2139] Primer 62: 4-[4-(6-ciklobutilsulfanil-piridin-2-il)-2,5-difluoro-fenoksi]-buterna kiselina[2139] Example 62: 4-[4-(6-cyclobutylsulfanyl-pyridin-2-yl)-2,5-difluoro-phenoxy]-butyric acid

[2140][2140]

[2142] [2142]

[2145] 2-hloro-6-ciklobutilsulfanil-piridin (0.081 g, 0.40 mmol) dobijen u primeru pripreme 19 i etil estar 4-[2,5-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenoksi]-buterne kiseline (0.14 g, 0.37 mmol) dobijen u fazi C primera pripreme 53 su korišćeni da bi sekvencijalno reagovali na isti način kao u fazi A primera 50 i fazi B primera 37 da bi se dobilo naslovno jedinjenje (0.057 g, 39 %).[2145] 2-chloro-6-cyclobutylsulfanyl-pyridine (0.081 g, 0.40 mmol) obtained in preparation example 19 and 4-[2,5-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-butyric acid ethyl ester (0.14 g, 0.37 mmol) obtained in phase C of preparation example 53 were used to react sequentially in the same manner as in Phase A of Example 50 and Phase B of Example 37 to give the title compound (0.057 g, 39 %).

[2146] 1H-NMR δ (CDCl<3>) 7.89(1H, m), 7.49(2H, m), 7.00(1H, m), 6.78(1H, m), 4.38(1H, m), 4.11(2H, m), 2.63(4H, m), 2.19(6H, m)[2146] 1H-NMR δ (CDCl<3>) 7.89(1H, m), 7.49(2H, m), 7.00(1H, m), 6.78(1H, m), 4.38(1H, m), 4.11(2H, m), 2.63(4H, m), 2.19(6H, m)

[2148] Primer 63: 4-[4-(2-tert-butilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina[2148] Example 63: 4-[4-(2-tert-butylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid

[2149][2149]

[2151] [2151]

[2154] 2-metil-propan-2-tiol (27 mg, 0.29 mmol) i etil estar 4-[2,6-difluoro-4-(2-fluoro-3-piridil)fenoksi]buterne kiseline (100 mg, 0.29 mmol) dobijen u primeru pripreme 109 su korišćeni da bi sekvencijalno reagovali na isti način kao u primeru pripreme 5 i fazi B primera 1 da bi se dobilo naslovno jedinjenje (55 mg, 46 %).[2154] 2-Methyl-propane-2-thiol (27 mg, 0.29 mmol) and 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butyric acid ethyl ester (100 mg, 0.29 mmol) obtained in Preparative Example 109 were used to react sequentially in the same manner as in Preparative Example 5 and Step B of Example 1 to give the title compound. (55 mg, 46 %).

[2155] 1H NMR (CDCl<3>) δ 8.45 (1H, m), 7.33 (1H, m), 7.04 (1H, m), 6.95 (2H, m), 4.27 (2H, t), 2.69 (2H, t), 2.15 (2H, m), 1.55 (9H, s)[2155] 1H NMR (CDCl<3>) δ 8.45 (1H, m), 7.33 (1H, m), 7.04 (1H, m), 6.95 (2H, m), 4.27 (2H, t), 2.69 (2H, t), 2.15 (2H, m), 1.55 (9H, s)

[2156] Primer 64: 6-[2,6-difluoro-4-(2-propilsulfanil-3-piridil)fenoksi] kapronska kiselina[2156] Example 64: 6-[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)phenoxy] caproic acid

[2157][2157]

[2159] [2159]

[2162] Faza A: etil 6-[2,6-difluoro-4-(2-propilsulfanil-3-piridil)fenoksi]heksanoat[2162] Phase A: ethyl 6-[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)phenoxy]hexanoate

[2163] 3-jodo-2-propilsulfanil-piridin (0.073 g, 0.26 mmol) dobijen u primeru pripreme 203 i etil 6-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]heksanoat (0.11 g, 0.27 mmol) dobijen u primeru pripreme 146 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.076 g, 69%).[2163] 3-iodo-2-propylsulfanyl-pyridine (0.073 g, 0.26 mmol) obtained in Preparation Example 203 and ethyl 6-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]hexanoate (0.11 g, 0.27 mmol) obtained in Preparation Example 146 were used. to react in the same manner as in Step A of Example 28 to give the title compound (0.076 g, 69%).

[2164] <1>H-NMR (CDCl<3>) δ 8.43 (1H, m), 7.33 (1H, m), 7.04 (1H, m), 7.00 (2H, m), 4.19 (2H, t), 4.13 (2H, q), 3.14 (2H, t), 2.34 (2H, t), 1.81 (2H, m), 1.73 (4H, m), 1.53 (2H, m), 1.28 (3H, t), 1.02 (3H, t)[2164] <1>H-NMR (CDCl<3>) δ 8.43 (1H, m), 7.33 (1H, m), 7.04 (1H, m), 7.00 (2H, m), 4.19 (2H, t), 4.13 (2H, q), 3.14 (2H, t), 2.34 (2H, t), 1.81 (2H, m), 1.73 (4H, m), 1.53 (2H, m), 1.28 (3H, t), 1.02 (3H, t)

[2166] Faza B: 6-[2,6-difluoro-4-(2-propilsulfanil-3-piridil)fenoksi]kapronska kiselina[2166] Phase B: 6-[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)phenoxy]caproic acid

[2167] Etil 6-[2,6-difluoro-4-(2-propilsulfanil-3-piridil)fenoksi]heksanoat (0.076 g, 0.18 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.068 g, 96%).[2167] Ethyl 6-[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)phenoxy]hexanoate (0.076 g, 0.18 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.068 g, 96%).

[2168] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.35 (1H, m), 7.04 (1H, m), 6.99 (2H, m), 4.20 (2H, t), 3.15 (2H, t), 2.42 (2H, t), 1.83 (2H, m), 1.72 (4H, m), 1.58 (2H, m), 1.02 (3H, t)[2168] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.35 (1H, m), 7.04 (1H, m), 6.99 (2H, m), 4.20 (2H, t), 3.15 (2H, t), 2.42 (2H, t), 1.83 (2H, m), 1.72 (4H, m), 1.58 (2H, m), 1.02 (3H, t)

[2170] Primer 65: 4-{2,6-difluoro-4-[6-(2-metil-propenil)-piridin-2-il]-fenoksi}-buterna kiselina[2170] Example 65: 4-{2,6-difluoro-4-[6-(2-methyl-propenyl)-pyridin-2-yl]-phenoxy}-butyric acid

[2171][2171]

[2173] [2173]

[2176] Faza A: etil estar 4-{2,6-difluoro-4-[6-(2-metil-propenil)-piridin-2-il]-fenoksi}-buterne kiseline [0862] Etil estar 4-[2,6-difluoro-4-(6-formil-piridin-2-il)-fenoksi]-buterne kiseline (0.25 g, 0.72 mmol) dobijen u primeru pripreme 57 je korišćen na isti način kao u primeru pripreme 101 da bi se dobilo naslovno jedinjenje (80 mg, 30 %).[2176] Phase A: 4-{2,6-difluoro-4-[6-(2-methyl-propenyl)-pyridin-2-yl]-phenoxy}-butyric acid ethyl ester [0862] 4-[2,6-difluoro-4-(6-formyl-pyridin-2-yl)-phenoxy]-butyric acid ethyl ester (0.25 g, 0.72 mmol) obtained in Preparation Example 57 was used in the same manner. as in Preparation Example 101 to give the title compound (80 mg, 30 %).

[2178] Faza B: 4-{2,6-difluoro-4-[6-(2-metil-propenil)-piridin-2-il]-fenoksi}-buterna kiselina[2178] Phase B: 4-{2,6-difluoro-4-[6-(2-methyl-propenyl)-pyridin-2-yl]-phenoxy}-butyric acid

[2179] Etil estar 4-{2,6-difluoro-4-[6-(2-metil-propenil)-piridin-2-il]-fenoksi}-buterne kiseline (20 mg, 0.05 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (17 mg, 97 %).[2179] 4-{2,6-difluoro-4-[6-(2-methyl-propenyl)-pyridin-2-yl]-phenoxy}-butyric acid ethyl ester (20 mg, 0.05 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (17 mg, 97%).

[2180] 1H NMR (CDCl<3>) δ 7.68 (1H, t), 7.62 (2H, m), 7.41 (1H, m), 7.10 (1H, d), 6.35 (1H, s), 4.25 (2H, t), 2.68 (2H, t), 2.21 (3H, s), 2.13 (2H, m), 1.98 (3H, s)[2180] 1H NMR (CDCl<3>) δ 7.68 (1H, t), 7.62 (2H, m), 7.41 (1H, m), 7.10 (1H, d), 6.35 (1H, s), 4.25 (2H, t), 2.68 (2H, t), 2.21 (3H, s), 2.13 (2H, m), 1.98 (3H, s)

[2182] Primer 66: 4-[2,6-difluoro-4-(6-izobutil-piridin-2-il)-fenoksi]-buterna kiselina[2182] Example 66: 4-[2,6-difluoro-4-(6-isobutyl-pyridin-2-yl)-phenoxy]-butyric acid

[2183][2183]

[2185] [2185]

[2188] Etil estar 4-{2,6-difluoro-4-[6-(2-metil-propenil)-piridin-2-il]-fenoksi}-buterne kiseline (60 mg, 0.16 mmol) dobijen u fazi A primera 65 je korišćen da bi reagovao sekvencijalno na isti način kao u fazi B primera pripreme 50 i fazi B primera 1 da bi se dobilo naslovno jedinjenje (40 mg, 86 %).[2188] 4-{2,6-Difluoro-4-[6-(2-methyl-propenyl)-pyridin-2-yl]-phenoxy}-butyric acid ethyl ester (60 mg, 0.16 mmol) obtained in Step A of Example 65 was used to react sequentially in the same manner as Step B of Preparation Example 50 and Step B of Example 1 to give the title compound (40 mg, 86%).

[2189] 1H NMR (CDCl<3>) δ 7.65 (1H, t), 7.59 (2H, m), 7.43 (1H, d), 7.06 (1H, d), 4.24 (2H, t), 2.70 (4H, m), 2.22 (1H, m), 2.12 (2H, m), 0.96 (6H, d)[2189] 1H NMR (CDCl<3>) δ 7.65 (1H, t), 7.59 (2H, m), 7.43 (1H, d), 7.06 (1H, d), 4.24 (2H, t), 2.70 (4H, m), 2.22 (1H, m), 2.12 (2H, m), 0.96 (6H, d)

[2191] Primer 67: 4-[4-(2-ciklobutilsulfanil-piridin-3-il)-3,5-difluoro-fenoksi]-buterna kiselina[2191] Example 67: 4-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-3,5-difluoro-phenoxy]-butyric acid

[2192][2192]

[2194] [2194]

[2197] 2-ciklobutilsulfanil-3-jodo-piridin (0.040 g, 0.14 mmol) dobijen u primeru pripreme 44 i etil estar 4-[3,5-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.051 g, 0.14 mmol) dobijen u primeru pripreme 54 su izreagovani na isti način kao u primeru 1 da bi se dobilo naslovno jedinjenje (0.005 g, 10 %).[2197] 2-cyclobutylsulfanyl-3-iodo-pyridine (0.040 g, 0.14 mmol) obtained in preparation example 44 and 4-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.051 g, 0.14 mmol) obtained in preparation example 54 were reacted in the same manner as in Example 1 to give the title compound (0.005 g, 10 %).

[2198] 1H NMR (CDCl<3>) δ 8.45 (1H, m), 7.37 (1H, m), 7.04 (1H, m), 6.56 (2H, m), 4.45 (1H, m), 4.06 (2H, t), 2.61 (2H, t), 2.59 (2H, m), 2.17 (2H, m), 2.05 (4H, m)[2198] 1H NMR (CDCl<3>) δ 8.45 (1H, m), 7.37 (1H, m), 7.04 (1H, m), 6.56 (2H, m), 4.45 (1H, m), 4.06 (2H, t), 2.61 (2H, t), 2.59 (2H, m), 2.17 (2H, m), 2.05 (4H, m)

[2200] Primer 68: 4-{2,6-difluoro-4-[2-(tetrahidro-piran-4-iloksi)-piridin-3-il]-fenoksi}-buterna kiselina [0871][2200] Example 68: 4-{2,6-difluoro-4-[2-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-phenoxy}-butyric acid [0871]

[2202] [2202]

[2203] 3-jodo-2-(tetrahidro-piran-4-iloksi)-piridin (0.040 g, 0.13 mmol) dobijen u primeru pripreme 58 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.049 g, 0.13 mmol) dobijen u primeru pripreme 2 su izreagovani na isti način kao u primeru 1 da bi se dobilo naslovno jedinjenje (0.035 g, 68 %).[2203] 3-iodo-2-(tetrahydro-pyran-4-yloxy)-pyridine (0.040 g, 0.13 mmol) obtained in preparation example 58 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.049 g, 0.13 mmol) obtained in preparation example 58 2 were reacted in the same manner as in Example 1 to give the title compound (0.035 g, 68 %).

[2204] 1H NMR (CDCl<3>) δ 8.12 (1H, m), 7.57 (1H, m), 7.14 (2H, m), 6.95 (1H, m), 5.37 (1H, m), 4.24 (2H, t), 3.90 (2H, m), 3.64 (2H, m), 2.67 (2H, t), 2.13 (4H, m), 1.82 (2H, m)[2204] 1H NMR (CDCl<3>) δ 8.12 (1H, m), 7.57 (1H, m), 7.14 (2H, m), 6.95 (1H, m), 5.37 (1H, m), 4.24 (2H, t), 3.90 (2H, m), 3.64 (2H, m), 2.67 (2H, t), 2.13 (4H, m), 1.82 (2H, m)

[2206] Primer 69: 4-{2,6-difluoro-4-[2-(tetrahidro-furan-3-iloksi)-piridin-3-il]-fenoksi}-buterna kiselina [0874][2206] Example 69: 4-{2,6-difluoro-4-[2-(tetrahydro-furan-3-yloxy)-pyridin-3-yl]-phenoxy}-butyric acid [0874]

[2208] [2208]

[2211] 3-jodo-2-(tetrahidro-furan-3-iloksi)-piridin (0.040 g, 0.14 mmol) dobijen u primeru pripreme 59 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.051 g, 0.14 mmol) dobijen u primeru pripreme 2 su izreagovani na isti način kao u primeru 1 da bi se dobilo naslovno jedinjenje (0.030 g, 58 %)[2211] 3-iodo-2-(tetrahydro-furan-3-yloxy)-pyridine (0.040 g, 0.14 mmol) obtained in preparation example 59 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.051 g, 0.14 mmol) obtained in preparation example 59 2 were reacted in the same manner as in Example 1 to give the title compound (0.030 g, 58 %)

[2212] 1H NMR (CDCl<3>) δ 8.12 (1H, m), 7.57 (1H, m), 7.13 (2H, m), 6.98 (1H, m), 5.63 (1H, m), 4.24 (2H, t), 4.07 (1H, m), 3.94 (3H, m), 2.68 (2H, t), 2.25 (1H, m), 2.14 (3H, m)[2212] 1H NMR (CDCl<3>) δ 8.12 (1H, m), 7.57 (1H, m), 7.13 (2H, m), 6.98 (1H, m), 5.63 (1H, m), 4.24 (2H, t), 4.07 (1H, m), 3.94 (3H, m), 2.68 (2H, t), 2.25 (1H, m), 2.14 (3H, m)

[2214] Primer 70: 4-[4-(2-ciklobutoksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina[2214] Example 70: 4-[4-(2-cyclobutoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid

[2215][2215]

[2217] [2217]

[2220] 2-ciklobutoksi-3-jodo-piridin (0.040 g, 0.15 mmol) dobijen u primeru pripreme 200 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.054 g, 0.15 mmol) dobijen u primeru pripreme 2 su izreagovani na isti način kao u primeru 1 da bi se dobilo naslovno jedinjenje (0.020 g, 38 %).[2220] 2-cyclobutoxy-3-iodo-pyridine (0.040 g, 0.15 mmol) obtained in preparation example 200 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.054 g, 0.15 mmol) obtained in preparation example 2 were reacted in the same manner as in Example 1 to obtain the title compound (0.020 g, 38 %).

[2221] 1H NMR (CDCl<3>) δ 8.12 (1H, m), 7.57 (1H, m), 7.18 (2H, m), 6.93 (1H, m), 5.28 (1H, m), 4.24 (2H, t), 2.69 (2H, t), 2.47 (2H, m), 2.12 (4H, m), 1.83 (1H, m), 1.69 (1H, m)[2221] 1H NMR (CDCl<3>) δ 8.12 (1H, m), 7.57 (1H, m), 7.18 (2H, m), 6.93 (1H, m), 5.28 (1H, m), 4.24 (2H, t), 2.69 (2H, t), 2.47 (2H, m), 2.12 (4H, m), 1.83 (1H, m), 1.69 (1H, m)

[2222] Primer 71: 4-{2,6-difluoro-4-[2-(2-metoksi-etoksi)-piridin-3-il]-fenoksi}-buterna kiselina[2222] Example 71: 4-{2,6-difluoro-4-[2-(2-methoxy-ethoxy)-pyridin-3-yl]-phenoxy}-butyric acid

[2223][2223]

[2225] [2225]

[2228] 2-metoksi-etanol (51 mg, 0.67 mmol) i 4-[2,6-difluoro-4-(2-fluoro-3-piridil)fenoksi]buterna kiselina (70 mg, 0.22 mmol) dobijena u primeru pripreme 56 su korišćeni da bi reagovali na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (55 mg, 67 %).[2228] 2-Methoxy-ethanol (51 mg, 0.67 mmol) and 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butyric acid (70 mg, 0.22 mmol) obtained in Preparative Example 56 were used to react in the same manner as in Preparative Example 37 to give the title compound (55 mg, 67%).

[2229] 1H NMR (CDCl<3>) δ 8.14 (1H, m), 7.59 (1H, m), 7.22 (2H, m), 6.96 (1H, m), 4.54 (2H, t), 4.24 (2H, t), 3.76 (2H, t), 3.42 (3H, s), 2.68 (2H, t), 2.12 (2H, m)[2229] 1H NMR (CDCl<3>) δ 8.14 (1H, m), 7.59 (1H, m), 7.22 (2H, m), 6.96 (1H, m), 4.54 (2H, t), 4.24 (2H, t), 3.76 (2H, t), 3.42 (3H, s), 2.68 (2H, t), 2.12 (2H, m)

[2231] Primer 72: 4-[2,6-difluoro-4-(2-pirolidin-1-il-3-piridil)fenoksi] buterna kiselina[2231] Example 72: 4-[2,6-difluoro-4-(2-pyrrolidin-1-yl-3-pyridyl)phenoxy]butyric acid

[2232][2232]

[2234] [2234]

[2237] Faza A: etil 4-[2,6-difluoro-4-(2-pirolidin-1-il-3-piridil)fenoksi]butanoat[2237] Phase A: ethyl 4-[2,6-difluoro-4-(2-pyrrolidin-1-yl-3-pyridyl)phenoxy]butanoate

[2238] 1.2 mL DMF-a je dodato u etil 4-[2,6-difluoro-4-(2-fluoro-3-piridil)fenoksi]butanoat (0.078 g, 0.23 mmol) dobijen u primeru pripreme 109, pirolidin (0.022 g, 0.32 mmol) i Cs<2>CO<3>(0.15 g, 0.46 mmol), i proizvod je mešan 8 sati na 50°C. Reakcioni rastvor je koncentrovana pod smanjenim pritiskom i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.056 g, 62%).[2238] 1.2 mL of DMF was added to ethyl 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butanoate (0.078 g, 0.23 mmol) obtained in Preparative Example 109, pyrrolidine (0.022 g, 0.32 mmol) and Cs<2>CO<3> (0.15 g, 0.46 mmol), and the product was stirred for 8 hours at 50°C. The reaction solution was concentrated under reduced pressure and purified by column chromatography to give the title compound (0.056 g, 62%).

[2239] <1>H-NMR (CDCl<3>) δ 8.16 (1H, m), 7.31 (1H, m), 6.90 (2H, m), 6.69 (1H, m), 4.21 (2H, t), 4.17 (2H, q), 3.15 (4H, m), 2.59 (2H, t), 2.12 (2H, m), 1.80 (4H, m), 1.27 (3H, t)[2239] <1>H-NMR (CDCl<3>) δ 8.16 (1H, m), 7.31 (1H, m), 6.90 (2H, m), 6.69 (1H, m), 4.21 (2H, t), 4.17 (2H, q), 3.15 (4H, m), 2.59 (2H, t), 2.12 (2H, m), 1.80 (4H, m), 1.27 (3H, t)

[2241] Faza B: 4-[2,6-difluoro-4-(2-pirolidin-1-il-3-piridil)fenoksi]buterna kiselina[2241] Phase B: 4-[2,6-difluoro-4-(2-pyrrolidin-1-yl-3-pyridyl)phenoxy]butyric acid

[2242] Etil 4-[2,6-difluoro-4-(2-pirolidin-1-il-3-piridil)fenoksi]butanoat (0.056 g, 0.14 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.038 g, 73%).[2242] Ethyl 4-[2,6-difluoro-4-(2-pyrrolidin-1-yl-3-pyridyl)phenoxy]butanoate (0.056 g, 0.14 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.038 g, 73%).

[2243] <1>H-NMR (CDCl<3>) δ 8.19 (1H, m), 7.33 (1H, m), 6.90 (2H, m), 6.70 (1H, m), 4.23 (2H, t), 3.17 (4H, m), 2.67 (2H, t), 2.12 (2H, m), 1.81 (4H, m)[2243] <1>H-NMR (CDCl<3>) δ 8.19 (1H, m), 7.33 (1H, m), 6.90 (2H, m), 6.70 (1H, m), 4.23 (2H, t), 3.17 (4H, m), 2.67 (2H, t), 2.12 (2H, m), 1.81 (4H, m)

[2244] Primer 73: 4-[4-[2-(ciklopentilamino)-3-piridil]-2,6-difluoro-fenoksi] buterna kiselina[2244] Example 73: 4-[4-[2-(cyclopentylamino)-3-pyridyl]-2,6-difluoro-phenoxy] butyric acid

[2245][2245]

[2247] [2247]

[2250] N-ciklopentil-3-jodo-piridin-2-amin (0.03 g, 0.1 mmol) dobijen u primeru pripreme 64 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.043 g, 0.11 mmol) dobijen u primeru pripreme 2 su korišćeni da bi sekvencijalno reagovali na isti način kao u fazi A primera 29 i fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.02 g, 50%).[2250] N-cyclopentyl-3-iodo-pyridin-2-amine (0.03 g, 0.1 mmol) obtained in Preparation Example 64 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.043 g, 0.11 mmol) obtained in Preparation Example 2 were used to would be reacted sequentially in the same manner as in Phase A of Example 29 and Phase B of Example 1 to give the title compound (0.02 g, 50%).

[2251] <1>H-NMR (CDCl<3>) δ 8.15 (1H, m), 7.19 (1H, m), 6.94 (2H, m), 6.60 (1H, m), 4.45 (1H, brs), 4.33 (1H, m), 4.25 (2H, t), 2.68 (2H, t), 2.15 (2H, m), 2.05 (2H, m), 1.64 (4H, m), 1.34 (2H, m)[2251] <1>H-NMR (CDCl<3>) δ 8.15 (1H, m), 7.19 (1H, m), 6.94 (2H, m), 6.60 (1H, m), 4.45 (1H, brs), 4.33 (1H, m), 4.25 (2H, t), 2.68 (2H, t), 2.15 (2H, m), 2.05 (2H, m), 1.64 (4H, m), 1.34 (2H, m)

[2253] Primer 74: 4-[4-[2-(ciklopropilmetilamino)-3-piridil]-2,6-difluoro-fenoksi]buterna kiselina[2253] Example 74: 4-[4-[2-(cyclopropylmethylamino)-3-pyridyl]-2,6-difluoro-phenoxy]butyric acid

[2254][2254]

[2256] [2256]

[2259] Faza A: etil 4-[4-[2-(ciklopropilmetilamino)-3-piridil]-2,6-difluoro-fenoksi]butanoat[2259] Phase A: ethyl 4-[4-[2-(cyclopropylmethylamino)-3-pyridyl]-2,6-difluoro-phenoxy]butanoate

[2260] Etil 4-[2,6-difluoro-4-(2-fluoro-3-piridil)fenoksi]butanoat (0.078 g, 0.23 mmol) dobijen u primeru pripreme 109 i tert-butil N-(ciklopropilmetil)karbamat(0.047g, 0.27mmol) su korišćeni da bi reagovali na isti način kao u fazi A primera 72 da bi se dobilo naslovno jedinjenje (0.025 g, 29%).[2260] Ethyl 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butanoate (0.078 g, 0.23 mmol) obtained in Preparation Example 109 and tert-butyl N-(cyclopropylmethyl)carbamate (0.047 g, 0.27 mmol) were used to react in the same manner as in Step A of Example 72 to give the title compound. (0.025 g, 29%).

[2261] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.21 (1H, m), 6.98 (2H, m), 6.62 (1H, m), 4.62 (1H, m), 4.24 (2H, t), 4.17 (2H, q), 3.26 (2H, m), 2.59 (2H, m), 2.12 (2H, m), 1.27 (3H, t), 1.05 (1H, m), 0.49 (2H, m), 0.20 (2H, m)[2261] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.21 (1H, m), 6.98 (2H, m), 6.62 (1H, m), 4.62 (1H, m), 4.24 (2H, t), 4.17 (2H, q), 3.26 (2H, m), 2.59 (2H, m), 2.12 (2H, m), 1.27 (3H, t), 1.05 (1H, m), 0.49 (2H, m), 0.20 (2H, m)

[2263] Faza B: 4-[4-[2-(ciklopropilmetilamino)-3-piridil]-2,6-difluoro-fenoksi] buterna kiselina[2263] Phase B: 4-[4-[2-(cyclopropylmethylamino)-3-pyridyl]-2,6-difluoro-phenoxy] butyric acid

[2264] Etil 4-[4-[2-(ciklopropilmetilamino)-3-piridil]-2,6-difluoro-fenoksi] butanoat (0.026 g, 0.066 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.02 g, 82%).[2264] Ethyl 4-[4-[2-(cyclopropylmethylamino)-3-pyridyl]-2,6-difluoro-phenoxy] butanoate (0.026 g, 0.066 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.02 g, 82%).

[2265] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.22 (1H, m), 6.99 (2H, m), 6.62 (1H, m), 4.64 (1H, brs), 4.24 (2H, t), 3.24 (2H, d), 2.63 (2H, t), 2.12 (2H, m), 1.05 (1H, m), 0.48 (2H, m), 0.20 (2H, m)[2265] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.22 (1H, m), 6.99 (2H, m), 6.62 (1H, m), 4.64 (1H, brs), 4.24 (2H, t), 3.24 (2H, d), 2.63 (2H, t), 2.12 (2H, m), 1.05 (1H, m), 0.48 (2H, m), 0.20 (2H, m)

[2266] Primer 75: 4-[4-[6-(ciklopropilmetilamino)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina[2266] Example 75: 4-[4-[6-(cyclopropylmethylamino)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid

[2267][2267]

[2269] [2269]

[2272] Faza A: etil 4-[4-[6-(ciklopropilmetilamino)-2-piridil]-2,6-difluoro-fenoksi]butanoat[2272] Phase A: ethyl 4-[4-[6-(cyclopropylmethylamino)-2-pyridyl]-2,6-difluoro-phenoxy]butanoate

[2273] 6-hloro-N-(ciklopropilmetil)piridin-2-amin (0.17 g, 0.93 mmol) dobijen u primeru pripreme 65 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.34 g, 0.93 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.125 g, 34%).[2273] 6-chloro-N-(cyclopropylmethyl)pyridin-2-amine (0.17 g, 0.93 mmol) obtained in Preparation Example 65 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.34 g, 0.93 mmol) obtained in Preparation Example 2 were used. to react in the same manner as in Step A of Example 29 to give the title compound (0.125 g, 34%).

[2274] <1>H-NMR (CDCl<3>) δ 7.54 (2H, m), 7.45 (1H, t), 6.91 (1H, d), 6.34 (1H, m), 4.70 (1H, m), 4.20 (2H, t), 4.15 (2H, q), 3.19 (2H, t), 2.58 (2H, t), 2.09 (2H, m), 1.28 (3H, t), 1.13 (1H, m), 0.55 (2H, m), 0.28 (2H, m)[2274] <1>H-NMR (CDCl<3>) δ 7.54 (2H, m), 7.45 (1H, t), 6.91 (1H, d), 6.34 (1H, m), 4.70 (1H, m), 4.20 (2H, t), 4.15 (2H, q), 3.19 (2H, t), 2.58 (2H, t), 2.09 (2H, m), 1.28 (3H, t), 1.13 (1H, m), 0.55 (2H, m), 0.28 (2H, m)

[2276] Faza B: 4-[4-[6-(ciklopropilmetilamino)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina[2276] Phase B: 4-[4-[6-(cyclopropylmethylamino)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid

[2277] Etil 4-[4-[6-(ciklopropilmetilamino)-2-piridil]-2,6-difluoro-fenoksi] butanoat (0.32 g, 0.34 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.115 g, 99%).[2277] Ethyl 4-[4-[6-(cyclopropylmethylamino)-2-pyridyl]-2,6-difluoro-phenoxy] butanoate (0.32 g, 0.34 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.115 g, 99%).

[2278] <1>H-NMR (CDCl<3>) δ 7.50 (3H, m), 6.90 (1H, d), 6.35 (1H, d), 4.22 (2H, t), 3.20 (2H, d), 2.66 (2H, t), 2.10 (2H, m), 1.12 (1H, m), 0.55 (2H, m), 0.29 (2H, m)[2278] <1>H-NMR (CDCl<3>) δ 7.50 (3H, m), 6.90 (1H, d), 6.35 (1H, d), 4.22 (2H, t), 3.20 (2H, d), 2.66 (2H, t), 2.10 (2H, m), 1.12 (1H, m), 0.55 (2H, m), 0.29 (2H, m)

[2280] Primer 76: 4-[2,6-difluoro-4-[2-(izopropilamino)-3-piridil]fenoksi] buterna kiselina[2280] Example 76: 4-[2,6-difluoro-4-[2-(isopropylamino)-3-pyridyl]phenoxy]butyric acid

[2281][2281]

[2283] [2283]

[2286] Faza A: etil 4-[2.6-difluoro-4-[2-(izopropilamino)-3-piridil]fenoksi]butanoat[2286] Phase A: Ethyl 4-[2,6-difluoro-4-[2-(isopropylamino)-3-pyridyl]phenoxy]butanoate

[2287] 3-jodo-N-izopropil-piridin-2-amin (0.045 g, 0.17 mmol) dobijen u primeru pripreme 66 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.063 g, 0.17 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.047 g, 74%).[2287] 3-iodo-N-isopropyl-pyridin-2-amine (0.045 g, 0.17 mmol) obtained in preparation example 66 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.063 g, 0.17 mmol) obtained in preparation example 2 were used to react in the same manner as in Step A of Example 29 to give the title compound (0.047 g, 74%).

[2288] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.19 (1H, m), 6.93 (2H, m), 6.60 (1H, m), 4.25 (4H, m), 4.17 (2H, q), 2.59 (2H, t), 2.12 (2H, m), 1.27 (3H, t), 1.20 (6H, d)[2288] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.19 (1H, m), 6.93 (2H, m), 6.60 (1H, m), 4.25 (4H, m), 4.17 (2H, q), 2.59 (2H, t), 2.12 (2H, m), 1.27 (3H, t), 1.20 (6H, d)

[2289] Faza B: 4-[2,6-difluoro-4-[2-(izopropilamino)-3-piridil]fenoksi]buterna kiselina[2289] Phase B: 4-[2,6-difluoro-4-[2-(isopropylamino)-3-pyridyl]phenoxy]butyric acid

[2290] Etil 4-[2,6-difluoro-4-[2-(izopropilamino)-3-piridil]fenoksi]butanoat (0.046 g, 0.12 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.023 g, 54%).[2290] Ethyl 4-[2,6-difluoro-4-[2-(isopropylamino)-3-pyridyl]phenoxy]butanoate (0.046 g, 0.12 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.023 g, 54%).

[2291] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.20 (1H, m), 6.95 (2H, m), 6.62 (1H, m), 4.25 (3H, m), 2.65 (2H, t), 2.13 (2H, m), 1.18 (6H, d)[2291] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.20 (1H, m), 6.95 (2H, m), 6.62 (1H, m), 4.25 (3H, m), 2.65 (2H, t), 2.13 (2H, m), 1.18 (6H, d)

[2293] Primer 77: 4-[4-[2-(ciklopropilamino)-3-piridil]-2,6-difluoro-fenoksi] buterna kiselina[2293] Example 77: 4-[4-[2-(cyclopropylamino)-3-pyridyl]-2,6-difluoro-phenoxy] butyric acid

[2294][2294]

[2296] [2296]

[2299] Faza A: etil 4-[4-[2-(ciklopropilamino)-3-piridil]-2,6-difluoro-fenoksi] butanoat[2299] Phase A: ethyl 4-[4-[2-(cyclopropylamino)-3-pyridyl]-2,6-difluoro-phenoxy] butanoate

[2300] N-ciklopropil-3-jodo-piridin-2-amin (0.05 g, 0.19 mmol) dobijen u primeru pripreme 67 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.07 g, 0.19 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.043 g, 60%).[2300] N-cyclopropyl-3-iodo-pyridin-2-amine (0.05 g, 0.19 mmol) obtained in Preparation Example 67 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.07 g, 0.19 mmol) obtained in Preparation Example 2 were used to reacted in the same manner as in Step A of Example 29 to give the title compound (0.043 g, 60%).

[2301] <1>H-NMR (CDCl<3>) δ 8.24 (1H, m), 7.22 (1H, m), 6.92 (2H, m), 6.69 (1H, m), 4.76 (1H, brs), 4.23 (2H, t), 4.16 (2H, q), 2.75 (1H, m), 2.58 (2H, t), 2.11 (2H, m), 1.27 (3H, t), 0.80 (2H, m), 0.47 (2H, m)[2301] <1>H-NMR (CDCl<3>) δ 8.24 (1H, m), 7.22 (1H, m), 6.92 (2H, m), 6.69 (1H, m), 4.76 (1H, brs), 4.23 (2H, t), 4.16 (2H, q), 2.75 (1H, m), 2.58 (2H, t), 2.11 (2H, m), 1.27 (3H, t), 0.80 (2H, m), 0.47 (2H, m)

[2303] Faza B: 4-[4-[2-(ciklopropilamino)-3-piridil]-2,6-difluoro-fenoksi]buterna kiselina[2303] Phase B: 4-[4-[2-(cyclopropylamino)-3-pyridyl]-2,6-difluoro-phenoxy]butyric acid

[2304] Etil 4-[4-[2-(ciklopropilamino)-3-piridil]-2,6-difluoro-fenoksi]butanoat (0.043 g, 0.11 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.015 g, 39%).[2304] Ethyl 4-[4-[2-(cyclopropylamino)-3-pyridyl]-2,6-difluoro-phenoxy]butanoate (0.043 g, 0.11 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.015 g, 39%).

[2305] <1>H-NMR (CDCl<3>) δ 8.25 (1H, m), 7.22 (1H, m), 6.90 (2H, m), 6.69 (1H, m), 4.82 (1H, brs), 4.25 (2H, t), 2.75 (1H, m), 2.66 (2H, t), 2.13 (2H, m), 0,80 (2H, m), 0.47 (2H, m)[2305] <1>H-NMR (CDCl<3>) δ 8.25 (1H, m), 7.22 (1H, m), 6.90 (2H, m), 6.69 (1H, m), 4.82 (1H, brs), 4.25 (2H, t), 2.75 (1H, m), 2.66 (2H, t), 2.13 (2H, m), 0.80 (2H, m), 0.47 (2H, m)

[2307] Primer 78: 4-[2,6-difluoro-4-[6-(izopropilamino)-2-piridil]fenoksi]buterna kiselina[2307] Example 78: 4-[2,6-difluoro-4-[6-(isopropylamino)-2-pyridyl]phenoxy]butyric acid

[2308][2308]

[2310] [2310]

[2313] Faza A: etil 4-[2,6-difluoro-4-[6-(izopropilamino)-2-piridil]fenoksi]butanoat[2313] Phase A: ethyl 4-[2,6-difluoro-4-[6-(isopropylamino)-2-pyridyl]phenoxy]butanoate

[2314] tert-butil N-(6-bromo-2-piridil)-N-izopropil-karbamat (0.06 g, 0.19 mmol) dobijen u primeru pripreme 69 je rastvoren u 0.4 mL TFA i 0.4 mL DCM-a, i proizvod je mešan na sobnoj temperaturi 5 sati. Reaktant koji je koncentrovan pod smanjenim pritiskom i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.07 g, 0.19 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.028 g, 39%).[2314] tert-butyl N-(6-bromo-2-pyridyl)-N-isopropyl-carbamate (0.06 g, 0.19 mmol) obtained in Preparative Example 69 was dissolved in 0.4 mL TFA and 0.4 mL DCM, and the product was stirred at room temperature for 5 hours. The reactant which was concentrated under reduced pressure and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.07 g, 0.19 mmol) obtained in Preparation Example 2 were used to react in the same manner as in Step A of Example 29 to give the title compound (0.028 g, 39%).

[2315] <1>H-NMR (CDCl<3>) δ 7.54 (2H, m), 7.45 (1H, t), 6.90 (1H, d), 6.31 (1H, d), 4.43 (1H, brs), 4.21 (2H, t), 4.15 (2H, q), 4.00 (1H, m), 2.58 (2H, t), 2.10 (2H, m), 1.26 (9H, m)[2315] <1>H-NMR (CDCl<3>) δ 7.54 (2H, m), 7.45 (1H, t), 6.90 (1H, d), 6.31 (1H, d), 4.43 (1H, brs), 4.21 (2H, t), 4.15 (2H, q), 4.00 (1H, m), 2.58 (2H, t), 2.10 (2H, m), 1.26 (9H, m)

[2317] Faza B: 4-[2,6-difluoro-4-[6-(izopropilamino)-2-piridil]fenoksi]buterna kiselina[2317] Phase B: 4-[2,6-difluoro-4-[6-(isopropylamino)-2-pyridyl]phenoxy]butyric acid

[2318] Etil 4-[2,6-difluoro-4-[6-(izopropilamino)-2-piridil]fenoksi]butanoat (0.028 g, 0.07 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.017 g, 65%).[2318] Ethyl 4-[2,6-difluoro-4-[6-(isopropylamino)-2-pyridyl]phenoxy]butanoate (0.028 g, 0.07 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.017 g, 65%).

[2319] <1>H-NMR (CDCl<3>) δ7.52 (2H, m), 7.46 (1H, t), 6.88 (1H, d), 6.33 (1H, d), 4.22 (2H, t), 3.97 (1H, m), 2.66 (2H, t), 2.10 (2H, m), 1.26 (6H, d)[2319] <1>H-NMR (CDCl<3>) δ7.52 (2H, m), 7.46 (1H, t), 6.88 (1H, d), 6.33 (1H, d), 4.22 (2H, t), 3.97 (1H, m), 2.66 (2H, t), 2.10 (2H, m), 1.26 (6H, d)

[2321] Primer 79: 4-[4-[2-(ciklopentilamino)fenil]-2,6-difluoro-fenoksi] buterna kiselina[2321] Example 79: 4-[4-[2-(cyclopentylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid

[2322][2322]

[2324] [2324]

[2327] Faza A: etil 4-[4-[2-(ciklopentilamino)fenil]-2,6-difluoro-fenoksi]butanoat[2327] Phase A: ethyl 4-[4-[2-(cyclopentylamino)phenyl]-2,6-difluoro-phenoxy]butanoate

[2328] N-ciklopentil-2-jodo-anilin (0.046 g, 0.16 mmol) dobijen u primeru pripreme 70 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.05 g, 0.135 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.044 g, 81%).[2328] N-cyclopentyl-2-iodo-aniline (0.046 g, 0.16 mmol) obtained in Preparation Example 70 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.05 g, 0.135 mmol) obtained in Preparation Example 2 were used to reacted in the same manner as in Step A of Example 28 to give the title compound (0.044 g, 81%).

[2329] <1>H-NMR (CDCl<3>) δ 7.21 (1H, t), 7.00 (3H, m), 6.71 (2H, m), 4.23 (2H, t), 4.15 (2H. q), 3.79 (2H, m), 2.60 (2H, t), 2.12 (2H, m), 1.98 (2H, m), 1.62 (4H, m), 1.41 (2H, m), 1.27 (3H, t)[2329] <1>H-NMR (CDCl<3>) δ 7.21 (1H, t), 7.00 (3H, m), 6.71 (2H, m), 4.23 (2H, t), 4.15 (2H, q), 3.79 (2H, m), 2.60 (2H, t), 2.12 (2H, m), 1.98 (2H, m), 1.62 (4H, m), 1.41 (2H, m), 1.27 (3H, t)

[2331] Faza B: 4-[4-[2-(ciklopentilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina[2331] Phase B: 4-[4-[2-(cyclopentylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid

[2332] Etil 4-[4-[2-(ciklopentilamino)fenil]-2,6-difluoro-fenoksi]butanoat (0.044 g, 0.11 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.035 g, 85%).[2332] Ethyl 4-[4-[2-(cyclopentylamino)phenyl]-2,6-difluoro-phenoxy]butanoate (0.044 g, 0.11 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.035 g, 85%).

[2333] <1>H-NMR (CDCl<3>) δ 7.21 (1H, t), 7.00 (1H, m), 6.98 (2H, m), 6.75 (2H, m), 4.24 (2H, t), 3.76 (1H, m), 2.68 (2H, t), 2.13 (2H, m), 1.99 (2H, m), 1.67 (2H, m), 1.60 (2H, m), 1.41 (2H, m)[2333] <1>H-NMR (CDCl<3>) δ 7.21 (1H, t), 7.00 (1H, m), 6.98 (2H, m), 6.75 (2H, m), 4.24 (2H, t), 3.76 (1H, m), 2.68 (2H, t), 2.13 (2H, m), 1.99 (2H, m), 1.67 (2H, m), 1.60 (2H, m), 1.41 (2H, m)

[2335] Primer 80: 4-[4-[3-(ciklopentilamino)fenil]-2,6-difluoro-fenoksi] buterna kiselina[2335] Example 80: 4-[4-[3-(cyclopentylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid

[2336][2336]

[2338] [2338]

[2341] Faza A: etil 4-{4-[3-(ciklopentilamino)fenil]-2,6-difluoro-fenoksi]butanoat[2341] Phase A: ethyl 4-{4-[3-(cyclopentylamino)phenyl]-2,6-difluoro-phenoxy]butanoate

[2342] 3-bromo-N-ciklopentil-anilin (0.039 g, 0.16 mmol) dobijen u primeru pripreme 71 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.05 g, 0.135 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.024 g, 44%).[2342] 3-Bromo-N-cyclopentyl-aniline (0.039 g, 0.16 mmol) obtained in Preparation Example 71 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.05 g, 0.135 mmol) obtained in Preparation Example 2 were used to reacted in the same manner as in Step A of Example 28 to give the title compound (0.024 g, 44%).

[2343] <1>H-NMR (CDCl<3>) δ 7.20 (1H, t), 7.07 (2H, m), 6.79 (1H, d), 6.68 (1H, m), 6.59 (1H, m), 4.20 (2H, t), 4.15 (2H, q), 3.85 (1H, m), 3.77 (1H, brs), 2.58 (2H, t), 2.10 (4H, m), 1.74 (2H, m), 1.65 (2H, m), 1.48 (2H, m), 1.27 (3H, t)[2343] <1>H-NMR (CDCl<3>) δ 7.20 (1H, t), 7.07 (2H, m), 6.79 (1H, d), 6.68 (1H, m), 6.59 (1H, m), 4.20 (2H, t), 4.15 (2H, q), 3.85 (1H, m), 3.77 (1H, brs), 2.58 (2H, t), 2.10 (4H, m), 1.74 (2H, m), 1.65 (2H, m), 1.48 (2H, m), 1.27 (3H, t)

[2345] Faza B: 4-[4-[3-(ciklopentilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina[2345] Phase B: 4-[4-[3-(cyclopentylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid

[2346] Etil 4-[4-[3-(ciklopentilamino)fenil]-2,6-difluoro-fenoksi]butanoat (0.024 g, 0.06 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.021 g, 94%).[2346] Ethyl 4-[4-[3-(cyclopentylamino)phenyl]-2,6-difluoro-phenoxy]butanoate (0.024 g, 0.06 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.021 g, 94%).

[2347] <1>H-NMR (CDCl<3>) δ 7.23 (1H, t), 7.09 (2H, m), 6.87 (1H, m), 6.82 (1H, m), 6.72 (1H, m), 4.21 (2H, t), 3.82 (1H, m), 2.67 (2H, t), 2.12 (2H, m), 2.04 (2H, m), 1.76 (2H, m), 1.63 (2H, m), 1.58 (2H, m)[2347] <1>H-NMR (CDCl<3>) δ 7.23 (1H, t), 7.09 (2H, m), 6.87 (1H, m), 6.82 (1H, m), 6.72 (1H, m), 4.21 (2H, t), 3.82 (1H, m), 2.67 (2H, t), 2.12 (2H, m), 2.04 (2H, m), 1.76 (2H, m), 1.63 (2H, m), 1.58 (2H, m)

[2349] Primer 81: 4-[2,6-difluoro-4-[2-(propilamino)fenil]fenoksi]buterna kiselina[2349] Example 81: 4-[2,6-difluoro-4-[2-(propylamino)phenyl]phenoxy]butyric acid

[2350][2350]

[2352] [2352]

[2355] Faza A: etil 4-[2,6-difluoro-4-[2-(propilamino)fenil]fenoksi]butanoat[2355] Phase A: Ethyl 4-[2,6-difluoro-4-[2-(propylamino)phenyl]phenoxy]butanoate

[2356] 2-jodo-N-propil-anilin (0.056 g, 0.21 mmol) dobijen u primeru pripreme 72 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.066 g, 0.18 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.048 g, 57%).[2356] 2-Iodo-N-propyl-aniline (0.056 g, 0.21 mmol) obtained in Preparation Example 72 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.066 g, 0.18 mmol) obtained in Preparation Example 2 were used to reacted in the same manner as in Step A of Example 28 to give the title compound (0.048 g, 57%).

[2357] <1>H-NMR (CDCl<3>) δ 7.25 (1H, t), 7.02 (1H, d), 6.99 (2H, m), 6.73 (1H, t), 6.69 (1H, d), 4.23 (2H, t), 4.16 (2H, q), 3.82 (1H, brs), 3.07 (2H, t), 2.59 (2H, t), 2.11 (2H, m), 1.62 (2H, m), 1.27 (3H, t), 0.96 (3H, t)[2357] <1>H-NMR (CDCl<3>) δ 7.25 (1H, t), 7.02 (1H, d), 6.99 (2H, m), 6.73 (1H, t), 6.69 (1H, d), 4.23 (2H, t), 4.16 (2H, q), 3.82 (1H, brs), 3.07 (2H, t), 2.59 (2H, t), 2.11 (2H, m), 1.62 (2H, m), 1.27 (3H, t), 0.96 (3H, t)

[2359] Faza B: 4-[2,6-difluoro-4-[2-(propilamino)fenil]fenoksi]buterna kiselina[2359] Phase B: 4-[2,6-difluoro-4-[2-(propylamino)phenyl]phenoxy]butyric acid

[2360] Etil 4-[2,6-difluoro-4-[2-(propilamino)fenil]fenoksi]butanoat (0.048 g, 0.12 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.023 g, 51%).[2360] Ethyl 4-[2,6-difluoro-4-[2-(propylamino)phenyl]phenoxy]butanoate (0.048 g, 0.12 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.023 g, 51%).

[2361] <1>H-NMR (CDCl<3>) δ 7.23 (1H, t), 7.00 (3H, m), 6.74 (1H, t), 6.69 (1H, d), 4.23 (2H, t), 3.07 (2H, t), 2.68 (2H, t), 2.13 (2H, m), 1.60 (2H, m), 0.94 (3H, t)[2361] <1>H-NMR (CDCl<3>) δ 7.23 (1H, t), 7.00 (3H, m), 6.74 (1H, t), 6.69 (1H, d), 4.23 (2H, t), 3.07 (2H, t), 2.68 (2H, t), 2.13 (2H, m), 1.60 (2H, m), 0.94 (3H, t)

[2363] Primer 82: 4-[4-[2-(ciklopropilmetilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina[2363] Example 82: 4-[4-[2-(cyclopropylmethylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid

[2364][2364]

[2366] [2366]

[2369] Faza A: etil 4-[4-[2-(ciklopropilmetilamino)fenil]-2,6-difluoro-fenil] butanoat[2369] Phase A: ethyl 4-[4-[2-(cyclopropylmethylamino)phenyl]-2,6-difluoro-phenyl] butanoate

[2370] N-(ciklopropilmetil)-2-jodo-anilin (0.059 g, 0.21 mmol) dobijen u primeru pripreme 73 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.066 g, 0.18 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.048 g, 58%).[2370] N-(cyclopropylmethyl)-2-iodo-aniline (0.059 g, 0.21 mmol) obtained in Preparation Example 73 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.066 g, 0.18 mmol) obtained in Preparation Example 2 were used to reacted in the same manner as in Step A of Example 28 to give the title compound (0.048 g, 58%).

[2371] <1>H-NMR (CDCl<3>) δ 7.22 (1H, t), 7.00 (3H, m), 6.74 (1H, t), 6.69 (1H, d), 4.23 (2H, t), 4.16 (2H, q), 3.97 (1H, brs), 2.96 (2H, d), 2.60 (2H, t), 2.12 (2H, m), 1.27 (3H, t), 1.04 (1H, m), 0.50 (2H, m), 0.18 (2H, m)[2371] <1>H-NMR (CDCl<3>) δ 7.22 (1H, t), 7.00 (3H, m), 6.74 (1H, t), 6.69 (1H, d), 4.23 (2H, t), 4.16 (2H, q), 3.97 (1H, brs), 2.96 (2H, d), 2.60 (2H, t), 2.12 (2H, m), 1.27 (3H, t), 1.04 (1H, m), 0.50 (2H, m), 0.18 (2H, m)

[2373] Faza B: 4-[4-[2-(ciklopropilmetilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina[2373] Phase B: 4-[4-[2-(cyclopropylmethylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid

[2374] Etil 4-[4-[2-(ciklopropilmetilamino)fenil]-2,6-difluoro-fenoksi] butanoat(0.048 g, 0.12 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje(0.042 g, 97%).[2374] Ethyl 4-[4-[2-(cyclopropylmethylamino)phenyl]-2,6-difluoro-phenoxy] butanoate (0.048 g, 0.12 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.042 g, 97%).

[2375] <1>H-NMR (CDCl<3>) δ 7.23 (1H, t), 7.00 (3H, m), 6.76 (1H, t), 6.70 (1H, d), 4.24 (2H, t), 2.96 (2H, d), 2.68 (2H, t), 2.13 (2H, m), 1.03 (1H, m), 0.52 (2H, m), 0.18 (2H, m)[2375] <1>H-NMR (CDCl<3>) δ 7.23 (1H, t), 7.00 (3H, m), 6.76 (1H, t), 6.70 (1H, d), 4.24 (2H, t), 2.96 (2H, d), 2.68 (2H, t), 2.13 (2H, m), 1.03 (1H, m), 0.52 (2H, m), 0.18 (2H, m)

[2376] Primer 83: 4-[2,6-difluoro-4-[2-(izopropilamino)fenil]fenoksi] buterna kiselina[2376] Example 83: 4-[2,6-difluoro-4-[2-(isopropylamino)phenyl]phenoxy]butyric acid

[2377][2377]

[2379] [2379]

[2382] Faza A: etil 4-[2,6-difluoro-4-[2-(izopropilamino)fenil]fenoksi]butanoat[2382] Phase A: Ethyl 4-[2,6-difluoro-4-[2-(isopropylamino)phenyl]phenoxy]butanoate

[2383] 2-jodo-N-izopropil-anilin (0.05 g, 0.19 mmol) dobijen u primeru pripreme 74 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.059 g, 0.16 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.043 g, 60%).[2383] 2-Iodo-N-isopropyl-aniline (0.05 g, 0.19 mmol) obtained in Preparation Example 74 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.059 g, 0.16 mmol) obtained in Preparation Example 2 were used to reacted in the same manner as in Step A of Example 28 to give the title compound (0.043 g, 60%).

[2384] <1>H-NMR (CDCl<3>) δ 7.22 (1H, t), 7.00 (1H, d), 6.95 (2H, m), 6.70 (2H, m), 4.23 (2H, t), 4.17 (2H, q), 3.03 (2H, m), 2.59 (2H, t), 2.11 (2H, m), 1.26 (3H, t), 1.17 (6H, d)[2384] <1>H-NMR (CDCl<3>) δ 7.22 (1H, t), 7.00 (1H, d), 6.95 (2H, m), 6.70 (2H, m), 4.23 (2H, t), 4.17 (2H, q), 3.03 (2H, m), 2.59 (2H, t), 2.11 (2H, m), 1.26 (3H, t), 1.17 (6H, d)

[2386] Faza B: 4-[2,6-difluoro-4-[2-(izopropilamino)fenil]fenoksi]buterna kiselina[2386] Phase B: 4-[2,6-difluoro-4-[2-(isopropylamino)phenyl]phenoxy]butyric acid

[2387] Etil 4-[2,6-difluoro-4-[2-(izopropilamino)fenil]fenoksi]butanoat (0.043 g, 0.11 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.038 g, 99%).[2387] Ethyl 4-[2,6-difluoro-4-[2-(isopropylamino)phenyl]phenoxy]butanoate (0.043 g, 0.11 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.038 g, 99%).

[2388] <1>H-NMR (CDCl<3>) δ 7.23 (1H, t), 7.00 (1H, d), 6.95 (2H, m), 6.72 (2H, m), 4.24 (2H, t), 3.63 (1H, m), 2.68 (2H, t), 2.13 (2H, m), 1.17 (6H, d)[2388] <1>H-NMR (CDCl<3>) δ 7.23 (1H, t), 7.00 (1H, d), 6.95 (2H, m), 6.72 (2H, m), 4.24 (2H, t), 3.63 (1H, m), 2.68 (2H, t), 2.13 (2H, m), 1.17 (6H, d)

[2390] Primer 84: 4-[4-[2-(ciklopentilamino)fenil]fenoksi]buterna kiselina[2390] Example 84: 4-[4-[2-(cyclopentylamino)phenyl]phenoxy]butyric acid

[2391][2391]

[2393] [2393]

[2396] N-ciklopentil-2-jodo-anilin (0.068 g, 0.24 mmol) dobijen u primeru pripreme 70 i etil estar 4-[4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksilbuterne kiseline (0.061 g, 0.18 mmol) dobijen u primeru pripreme 1 su korišćeni da bi sekvencijalno reagovali na isti način kao u fazi A primera 28 i fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.01g, 15%).[2396] N-cyclopentyl-2-iodo-aniline (0.068 g, 0.24 mmol) obtained in Preparation Example 70 and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxybutyric acid ethyl ester (0.061 g, 0.18 mmol) obtained in Preparation Example 1 were used to react sequentially in the same manner. as in Phase A of Example 28 and Phase B of Example 1 to give the title compound (0.01g, 15%).

[2397] <1>H-NMR (CDCl<3>) δ 7.31 (2H, m), 7.20 (1H, t), 7.02 (1H, d), 6.95 (2H, m), 6.72 (2H, m), 4.07 (2H, t), 3.78 (1H, m), 2.62 (2H, t), 2.17 (2H, m), 1.95 (2H, m), 1.58 (4H, m), 1.38 (2H, m)[2397] <1>H-NMR (CDCl<3>) δ 7.31 (2H, m), 7.20 (1H, t), 7.02 (1H, d), 6.95 (2H, m), 6.72 (2H, m), 4.07 (2H, t), 3.78 (1H, m), 2.62 (2H, t), 2.17 (2H, m), 1.95 (2H, m), 1.58 (4H, m), 1.38 (2H, m)

[2398] Primer 85: 4-[4-[2-(ciklopropilmetilamino)fenil]fenoksi]buterna kiselina[2398] Example 85: 4-[4-[2-(cyclopropylmethylamino)phenyl]phenoxy]butyric acid

[2399][2399]

[2401] [2401]

[2404] N-(ciklopropilmetil)-2-jodo-anilin (0.057 g, 0.21 mmol) dobijen u primeru pripreme 73 i etil estar 4-[4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksilbuterne kiseline (0.061 g, 0.18 mmol) dobijen u primeru pripreme 1 su korišćeni da bi sekvencijalno reagovali na isti način kao u fazi A primera 28 i fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.015g, 23%).[2404] N-(cyclopropylmethyl)-2-iodo-aniline (0.057 g, 0.21 mmol) obtained in Preparation Example 73 and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxybutyric acid ethyl ester (0.061 g, 0.18 mmol) obtained in Preparation Example 1 were used to sequentially react with manner as in Phase A of Example 28 and Phase B of Example 1 to give the title compound (0.015g, 23%).

[2405] <1>H-NMR (CDCl<3>) δ 7.35 (2H, m), 7.20 (1H, t), 7.06 (1H, m), 6.97 (2H, m), 6.73 (1H, t), 6.68 (1H, d), 4.07 (2H, t), 2.95 (2H, d), 2.63 (2H, m), 2.16 (2H, m), 1.02 (1H, m), 0.47 (2H, m), 0.15 (2H, m)[2405] <1>H-NMR (CDCl<3>) δ 7.35 (2H, m), 7.20 (1H, t), 7.06 (1H, m), 6.97 (2H, m), 6.73 (1H, t), 6.68 (1H, d), 4.07 (2H, t), 2.95 (2H, d), 2.63 (2H, m), 2.16 (2H, m), 1.02 (1H, m), 0.47 (2H, m), 0.15 (2H, m)

[2407] Primer 86: 4-[4-[2-(propilamino)fenil]fenoksi]buterna kiselina[2407] Example 86: 4-[4-[2-(propylamino)phenyl]phenoxy]butyric acid

[2408][2408]

[2410] [2410]

[2413] 2-jodo-N-propil-anilin (0.056 g, 0.21 mmol) dobijen u primeru pripreme 72 i etil estar 4-[4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.061 g, 0.18 mmol) dobijen u primeru pripreme 1 su korišćeni da bi sekvencijalno reagovali na isti način kao u fazi A primera 28 i fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.007 g, 11%).[2413] 2-Iodo-N-propyl-aniline (0.056 g, 0.21 mmol) obtained in Preparation Example 72 and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.061 g, 0.18 mmol) obtained in Preparation Example 1 were used to react sequentially in the same manner. as in Phase A of Example 28 and Phase B of Example 1 to give the title compound (0.007 g, 11%).

[2414] <1>H-NMR (CDCl<3>) δ 7.32 (2H, m), 7.21 (1H, t), 7.05 (1H, d), 6.95 (2H, m), 6.72 (1H, t), 6.68 (1H, d), 4.07 (2H, t), 3.05 (2H, t), 2.62 (2H, t), 2.17 (2H, m), 1.55 (2H, m), 0.91 (3H, t)[2414] <1>H-NMR (CDCl<3>) δ 7.32 (2H, m), 7.21 (1H, t), 7.05 (1H, d), 6.95 (2H, m), 6.72 (1H, t), 6.68 (1H, d), 4.07 (2H, t), 3.05 (2H, t), 2.62 (2H, t), 2.17 (2H, m), 1.55 (2H, m), 0.91 (3H, t)

[2416] Primer 87: 4-[4-[2-(izopropilamino)fenil]fenoksi]buterna kiselina[2416] Example 87: 4-[4-[2-(isopropylamino)phenyl]phenoxy]butyric acid

[2417][2417]

[2419] [2419]

[2422] 2-jodo-N-izopropil-anilin (0.05 g, 0.19 mmol) dobijen u primeru pripreme 74 i etil estar 4-[4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.053 g, 0.16 mmol) dobijen u primeru pripreme 1 su korišćeni da bi sekvencijalno reagovali na isti način kao u fazi A primera 28 i fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.008 g, 15%).[2422] 2-Iodo-N-isopropyl-aniline (0.05 g, 0.19 mmol) obtained in Preparation Example 74 and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.053 g, 0.16 mmol) obtained in Preparation Example 1 were used to react sequentially in the same manner. as in Phase A of Example 28 and Phase B of Example 1 to give the title compound (0.008 g, 15%).

[2423] <1>H-NMR (CDCl<3>) δ 7.30 (2H, m), 7.19 (1H, t), 7.04 (1H, d), 6.95 (2H, m), 6.69 (2H, m), 4.07 (2H, t), 3.63 (1H, m), 2.63 (2H, t), 2.16 (2H, m), 1.14 (6H, d)[2423] <1>H-NMR (CDCl<3>) δ 7.30 (2H, m), 7.19 (1H, t), 7.04 (1H, d), 6.95 (2H, m), 6.69 (2H, m), 4.07 (2H, t), 3.63 (1H, m), 2.63 (2H, t), 2.16 (2H, m), 1.14 (6H, d)

[2425] Primer 88: 4-[4-[2-(ciklobutilamino)fenil]fenoksi]buterna kiselina[2425] Example 88: 4-[4-[2-(cyclobutylamino)phenyl]phenoxy]butyric acid

[2426][2426]

[2428] [2428]

[2431] 2-bromo-N-ciklobutil-anilin (0.07 g, 0.21 mmol)dobijen u primeru pripreme 75 i etil estar 4-[4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksilbuterne kiseline (0.095 g, 0.42 mmol) dobijen u primeru pripreme 1 su korišćeni da bi sekvencijalno reagovali na isti način kao u fazi A primera 28 i fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.007 g, 0.1%).[2431] 2-Bromo-N-cyclobutyl-aniline (0.07 g, 0.21 mmol) obtained in Preparation Example 75 and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxybutyric acid ethyl ester (0.095 g, 0.42 mmol) obtained in Preparation Example 1 were used to react sequentially in the same manner as in Phase A of Example 28 and Phase B of Example 1 to give the title compound (0.007 g, 0.1%).

[2432] <1>H-NMR (CDCl<3>) δ 7.33 (2H, m), 7.19 (1H, t), 7.06 (1H, d), 6.97 (2H, m), 6.73 (1H, t), 6.58 (1H, d), 4.12 (2H, t), 3.91 (1H, m), 2.63 (2H, t), 2.36 (2H, m), 2.17 (2H, m), 1.75 (4H, m)[2432] <1>H-NMR (CDCl<3>) δ 7.33 (2H, m), 7.19 (1H, t), 7.06 (1H, d), 6.97 (2H, m), 6.73 (1H, t), 6.58 (1H, d), 4.12 (2H, t), 3.91 (1H, m), 2.63 (2H, t), 2.36 (2H, m), 2.17 (2H, m), 1.75 (4H, m)

[2434] Primer 89: 4-[4-[2-(ciklobutilamino)fenil]-2,6-difluoro-fenoksi] buterna kiselina[2434] Example 89: 4-[4-[2-(cyclobutylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid

[2435][2435]

[2437] [2437]

[2440] 2-bromo-N-ciklobutil-anilin (0.136 g, 0.6 mmol) dobijen u primeru pripreme 75 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.1 g, 0.27 mmol) dobijen u primeru pripreme 2 su korišćeni da bi sekvencijalno reagovali na isti način kao u fazi A primera 28 i fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.004 g, 0.04%).[2440] 2-Bromo-N-cyclobutyl-aniline (0.136 g, 0.6 mmol) obtained in Preparation Example 75 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.1 g, 0.27 mmol) obtained in Preparation Example 2 were used to sequentially reacted in the same manner as in Phase A of Example 28 and Phase B of Example 1 to give the title compound (0.004 g, 0.04%).

[2441] <1>H-NMR (CDCl<3>) δ 7.21 (1H, t), 6.99 (3H, m), 6.73 (1H, t), 6.58 (1H, d), 4.24 (2H, t), 3.89 (1H, m), 2.68 (2H, t), 2.40 (2H, m), 2.13 (2H, m), 1.77 (4H, m)[2441] <1>H-NMR (CDCl<3>) δ 7.21 (1H, t), 6.99 (3H, m), 6.73 (1H, t), 6.58 (1H, d), 4.24 (2H, t), 3.89 (1H, m), 2.68 (2H, t), 2.40 (2H, m), 2.13 (2H, m), 1.77 (4H, m)

[2442] Primer 90: 4-[4-[3-(ciklopropilmetilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina[2442] Example 90: 4-[4-[3-(cyclopropylmethylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid

[2443][2443]

[2445] [2445]

[2448] Faza A: etil 4-[4-[3-(ciklopropilmetilamino)fenil]-2,6-difluoro-fenoksi] butanoat[2448] Phase A: ethyl 4-[4-[3-(cyclopropylmethylamino)phenyl]-2,6-difluoro-phenoxy] butanoate

[2449] 3-bromo-N-(ciklopropilmetil)anilin (0.063 g, 0.23 mmol) dobijen u primeru pripreme 76 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.072 g, 0.19 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.04 g, 54%).[2449] 3-Bromo-N-(cyclopropylmethyl)aniline (0.063 g, 0.23 mmol) obtained in Preparation Example 76 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.072 g, 0.19 mmol) obtained in Preparation Example 2 were used to reacted in the same manner as in Step A of Example 29 to give the title compound (0.04 g, 54%).

[2450] <1>H-NMR (CDCl<3>) δ 7.21 (1H, t), 7.09 (2H, m), 6.80 (1H, d), 6.70 (1H, m), 6.60 (1H, m), 4.18 (4H, m), 3.95 (1H, brs), 3.00 (2H, d), 2.59 (2H, t), 2.10 (2H, m), 1.27 (3H, t), 1.10 (1H, m), 0.57 (2H, m), 0.26 (2H, m)[2450] <1>H-NMR (CDCl<3>) δ 7.21 (1H, t), 7.09 (2H, m), 6.80 (1H, d), 6.70 (1H, m), 6.60 (1H, m), 4.18 (4H, m), 3.95 (1H, brs), 3.00 (2H, d), 2.59 (2H, t), 2.10 (2H, m), 1.27 (3H, t), 1.10 (1H, m), 0.57 (2H, m), 0.26 (2H, m)

[2452] Faza B: 4-[4-[3-(ciklopropilmetilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina[2452] Phase B: 4-[4-[3-(cyclopropylmethylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid

[2453] Etil 4-[4-[3-(ciklopropilmetilamino)fenil]-2,6-difluoro-fenoksi] butanoat (0.04 g, 0.1 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.026 g, 72%).[2453] Ethyl 4-[4-[3-(cyclopropylmethylamino)phenyl]-2,6-difluoro-phenoxy] butanoate (0.04 g, 0.1 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.026 g, 72%).

[2454] <1>H-NMR (CDCl<3>) δ 7.21 (1H, t), 7.11 (2H, m), 6.80 (1H, d), 6.70 (1H, m), 6.61 (1H, m), 4.21 (2H, t), 3.00 (2H, d), 2.67 (2H, t), 2.12 (2H, m), 1.18 (1H, m), 0.57 (2H, m), 0.27 (2H, m)[2454] <1>H-NMR (CDCl<3>) δ 7.21 (1H, t), 7.11 (2H, m), 6.80 (1H, d), 6.70 (1H, m), 6.61 (1H, m), 4.21 (2H, t), 3.00 (2H, d), 2.67 (2H, t), 2.12 (2H, m), 1.18 (1H, m), 0.57 (2H, m), 0.27 (2H, m)

[2456] Primer 91: 4-[2,6-difluoro-4-[3-(izopropilamino)fenil]fenoksi] buterna kiselina[2456] Example 91: 4-[2,6-difluoro-4-[3-(isopropylamino)phenyl]phenoxy]butyric acid

[2457][2457]

[2459] [2459]

[2462] Faza A: etil 4-[2,6-difluoro-4-[3-(izopropilamino)fenil]fenoksi]butanoat[2462] Phase A: ethyl 4-[2,6-difluoro-4-[3-(isopropylamino)phenyl]phenoxy]butanoate

[2463] 3-bromo-N-izopropil-anilin (0.06 g, 0.23 mmol) dobijen u primeru pripreme 77 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.072 g, 0.19 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.043 g, 60%).[2463] 3-Bromo-N-isopropyl-aniline (0.06 g, 0.23 mmol) obtained in Preparation Example 77 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.072 g, 0.19 mmol) obtained in Preparation Example 2 were used to react in the same manner as in Step A of Example 29 to give the title compound (0.043 g, 60%).

[2464] <1>H-NMR (CDCl<3>) δ 7.20 (1H, t), 7.09 (2H, m), 6.78 (1H, d), 6.66 (1H, m), 6.57 (1H, m), 4.18 (4H, m), 3.68 (1H, m), 3.60 (1H, brs), 2.59 (2H, t), 2.12 (2H, m), 1.27 (9H, m)[2464] <1>H-NMR (CDCl<3>) δ 7.20 (1H, t), 7.09 (2H, m), 6.78 (1H, d), 6.66 (1H, m), 6.57 (1H, m), 4.18 (4H, m), 3.68 (1H, m), 3.60 (1H, brs), 2.59 (2H, t), 2.12 (2H, m), 1.27 (9H, m)

[2465] Faza B: 4-[2,6-difluoro-4-[3-(izopropilamino)fenil]fenoksi]buterna kiselina[2465] Phase B: 4-[2,6-difluoro-4-[3-(isopropylamino)phenyl]phenoxy]butyric acid

[2466] Etil 4-[2,6-difluoro-4-[3-(izopropilamino)fenil]fenoksi]butanoat (0.043 g, 0.11 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.032 g, 83%).[2466] Ethyl 4-[2,6-difluoro-4-[3-(isopropylamino)phenyl]phenoxy]butanoate (0.043 g, 0.11 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.032 g, 83%).

[2467] <1>H-NMR (CDCl<3>) δ 7.20 (1H, t), 7.10 (2H, m), 6.78 (1H, d), 6.67 (1H, m), 6.58 (1H, m), 4.21 (2H, t), 3.69 (1H, m), 2.67 (2H, t), 2.11 (2H, m), 1.24 (6H, d)[2467] <1>H-NMR (CDCl<3>) δ 7.20 (1H, t), 7.10 (2H, m), 6.78 (1H, d), 6.67 (1H, m), 6.58 (1H, m), 4.21 (2H, t), 3.69 (1H, m), 2.67 (2H, t), 2.11 (2H, m), 1.24 (6H, d)

[2469] Primer 92: 4-[2,6-difluoro-4-(3-pirolidin-1-ilfenil)fenoksi]buterna kiselina[2469] Example 92: 4-[2,6-difluoro-4-(3-pyrrolidin-1-ylphenyl)phenoxy]butyric acid

[2470][2470]

[2472] [2472]

[2475] Faza A: etil 4-[2,6-difluoro-4-(3-pirolidin-1-ilfenil)fenoksi]butanoat[2475] Phase A: Ethyl 4-[2,6-difluoro-4-(3-pyrrolidin-1-ylphenyl)phenoxy]butanoate

[2476] 1-(3-bromofenil)pirolidin (0.039 g, 0.17 mmol) dobijen u primeru pripreme 78 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.053 g, 0.14 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.037 g, 60%).[2476] 1-(3-Bromophenyl)pyrrolidine (0.039 g, 0.17 mmol) obtained in Preparation Example 78 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.053 g, 0.14 mmol) obtained in Preparation Example 2 were used to react in the same manner as in Step A of Example 29 to give the title compound (0.037 g, 60%).

[2477] <1>H-NMR (CDCl<3>) δ 7.26 (1H, m), 7.13 (2H, m), 6.77 (1H, d), 6.63 (1H, m), 6.57 (1H, m), 4.18 (4H, m), 3.33 (4H, m), 2.59 (2H, t), 2.11 (2H, m), 2.03 (4H, m), 1.26 (3H, t)[2477] <1>H-NMR (CDCl<3>) δ 7.26 (1H, m), 7.13 (2H, m), 6.77 (1H, d), 6.63 (1H, m), 6.57 (1H, m), 4.18 (4H, m), 3.33 (4H, m), 2.59 (2H, t), 2.11 (2H, m), 2.03 (4H, m), 1.26 (3H, t)

[2479] Faza B: 4-[2,6-difluoro-4-(3-pirolidin-1-ilfenil)fenoksi]buterna kiselina[2479] Phase B: 4-[2,6-difluoro-4-(3-pyrrolidin-1-ylphenyl)phenoxy]butyric acid

[2480] Etil 4-[2,6-difluoro-4-(3-pirolidin-1-ilfenil)fenoksi]butanoat (0.033 g, 0.09 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.014 g, 45%).[2480] Ethyl 4-[2,6-difluoro-4-(3-pyrrolidin-1-ylphenyl)phenoxy]butanoate (0.033 g, 0.09 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.014 g, 45%).

[2481] <1>H-NMR (CDCl<3>) δ 7.26 (1H, m), 7.14 (2H, m), 6.76 (1H, d), 6.62 (1H, m), 6.58 (1H, m), 4.21 (2H, t), 3.33 (4H, m), 2.67 (2H, t), 2.12 (2H, m), 2.03 (4H, m)[2481] <1>H-NMR (CDCl<3>) δ 7.26 (1H, m), 7.14 (2H, m), 6.76 (1H, d), 6.62 (1H, m), 6.58 (1H, m), 4.21 (2H, t), 3.33 (4H, m), 2.67 (2H, t), 2.12 (2H, m), 2.03 (4H, m)

[2483] Primer 93: 4-[4-[3-(ciklobutilamino)fenil]-2,6-difluoro-fenoksi] buterna kiselina[2483] Example 93: 4-[4-[3-(cyclobutylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid

[2484][2484]

[2486] [2486]

[2487] Faza A: etil 4-[4-[3-(ciklobutilamino)fenil]-2,6-difluoro-fenoksi]butanoat[2487] Phase A: ethyl 4-[4-[3-(cyclobutylamino)phenyl]-2,6-difluoro-phenoxy]butanoate

[2488] 3-bromo-N-ciklobutil-anilin (0.028 g, 0.12 mmol) dobijen u primeru pripreme 80 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.045 g, 0.12 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.019 g, 40%).[2488] 3-Bromo-N-cyclobutyl-aniline (0.028 g, 0.12 mmol) obtained in Preparation Example 80 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.045 g, 0.12 mmol) obtained in Preparation Example 2 were used to prepare reacted in the same manner as in Step A of Example 29 to give the title compound (0.019 g, 40%).

[2489] <1>H-NMR (CDCl<3>) δ 7.19 (1H, t), 7.10 (2H, m), 6.81 (1H, d), 6.63 (1H, m), 6.55 (1H, m), 4.20 (2H, t), 4.14 (2H, q), 3.95 (2H, m), 2.60 (2H, t), 2.44 (2H, m), 2.10 (2H, m), 1.85 (4H, m), 1.27 (3H, t)[2489] <1>H-NMR (CDCl<3>) δ 7.19 (1H, t), 7.10 (2H, m), 6.81 (1H, d), 6.63 (1H, m), 6.55 (1H, m), 4.20 (2H, t), 4.14 (2H, q), 3.95 (2H, m), 2.60 (2H, t), 2.44 (2H, m), 2.10 (2H, m), 1.85 (4H, m), 1.27 (3H, t)

[2491] Faza B: 4-[4-[3-(ciklobutilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina[2491] Phase B: 4-[4-[3-(cyclobutylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid

[2492] Etil 4-[4-[3-(ciklobutilamino)fenil]-2,6-difluoro-fenoksi]butanoat (0.019 g, 0.05 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.014 g, 77%).[2492] Ethyl 4-[4-[3-(cyclobutylamino)phenyl]-2,6-difluoro-phenoxy]butanoate (0.019 g, 0.05 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.014 g, 77%).

[2493] <1>H-NMR (CDCl<3>) δ 7.20 (1H, t), 7.07 (2H, m), 6.81 (1H, d), 6.63 (1H, m), 6.54 (1H, m), 4.21 (2H, t), 3.96 (1H, m), 2.67 (2H, t), 2.45 (2H, m), 2.11 (2H, m), 1.84 (4H, m)[2493] <1>H-NMR (CDCl<3>) δ 7.20 (1H, t), 7.07 (2H, m), 6.81 (1H, d), 6.63 (1H, m), 6.54 (1H, m), 4.21 (2H, t), 3.96 (1H, m), 2.67 (2H, t), 2.45 (2H, m), 2.11 (2H, m), 1.84 (4H, m)

[2495] Primer 94: 4-[2,6-difluoro-4-[3-(propilamino)fenil]fenoksi]buterna kiselina[2495] Example 94: 4-[2,6-difluoro-4-[3-(propylamino)phenyl]phenoxy]butyric acid

[2496][2496]

[2498] [2498]

[2501] Faza A: etil 4-[2,6-difluoro-4-[3-(propilamino)fenil]fenoksi]butanoat[2501] Phase A: ethyl 4-[2,6-difluoro-4-[3-(propylamino)phenyl]phenoxy]butanoate

[2502] 3-bromo-N-propil-anilin (0.07 g, 0.3 mmol) dobijen u primeru pripreme 79 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.08 g, 0.21 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.029 g, 37%).[2502] 3-Bromo-N-propyl-aniline (0.07 g, 0.3 mmol) obtained in Preparation Example 79 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.08 g, 0.21 mmol) obtained in Preparation Example 2 were used to react in the same manner. as in Step A of Example 29 to give the title compound (0.029 g, 37%).

[2503] <1>H-NMR (CDCl<3>) δ 7.21 (1H, t), 7.09 (2H, m), 6.80 (1H, d), 6.69 (1H, m), 6.61 (1H, m), 4.20 (2H, t), 4.14 (2H, q), 3.75 (1H, brs), 3.13 (2H, t), 2.58 (2H, t), 2.10 (2H, m), 1.66 (2H, m), 1.27 (3H, t), 1.02 (3H, t)[2503] <1>H-NMR (CDCl<3>) δ 7.21 (1H, t), 7.09 (2H, m), 6.80 (1H, d), 6.69 (1H, m), 6.61 (1H, m), 4.20 (2H, t), 4.14 (2H, q), 3.75 (1H, brs), 3.13 (2H, t), 2.58 (2H, t), 2.10 (2H, m), 1.66 (2H, m), 1.27 (3H, t), 1.02 (3H, t)

[2505] Faza B: 4-[2,6-difluoro-4-[3-(propilamino)fenil]fenoksi]buterna kiselina[2505] Phase B: 4-[2,6-difluoro-4-[3-(propylamino)phenyl]phenoxy]butyric acid

[2506] Etil 4-[2,6-difluoro-4-[3-(propilamino)fenil]fenoksi]butanoat (0.029 g, 0.076 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.021 g, 78%).[2506] Ethyl 4-[2,6-difluoro-4-[3-(propylamino)phenyl]phenoxy]butanoate (0.029 g, 0.076 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.021 g, 78%).

[2507] <1>H-NMR (CDCl<3>) δ 7.21 (1H, t), 7.11 (2H, m), 6.80 (1H, d), 6.69 (1H, m), 6.60 (1H, m), 4.21 (2H, t), 3.13 (2H, t), 2.67 (2H, t), 2.11 (2H, m), 1.66 (2H, m), 1.02 (3H, t)[2507] <1>H-NMR (CDCl<3>) δ 7.21 (1H, t), 7.11 (2H, m), 6.80 (1H, d), 6.69 (1H, m), 6.60 (1H, m), 4.21 (2H, t), 3.13 (2H, t), 2.67 (2H, t), 2.11 (2H, m), 1.66 (2H, m), 1.02 (3H, t)

[2508] Primer 95: 4-[4-[5-hloro-2-(ciklopentilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina[2508] Example 95: 4-[4-[5-chloro-2-(cyclopentylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid

[2509][2509]

[2511] [2511]

[2514] Faza A: etil 4-[4-[5-hloro-2-(ciklopentilamino)fenil]-2,6-difluoro-fenoksi]butanoat[2514] Phase A: ethyl 4-[4-[5-chloro-2-(cyclopentylamino)phenyl]-2,6-difluoro-phenoxy]butanoate

[2515] 2-bromo-4-hloro-N-ciklopentil-anilin (0.083 g, 0.3 mmol)dobijen u primeru pripreme 81 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.112 g, 0.3 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.1 g, 76%).[2515] 2-bromo-4-chloro-N-cyclopentyl-aniline (0.083 g, 0.3 mmol) obtained in preparation example 81 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.112 g, 0.3 mmol) obtained in preparation example 2 were used to react in the same manner as in Step A of Example 28 to give the title compound (0.1 g, 76%).

[2516] <1>H-NMR (CDCl<3>) δ 7.16 (1H, m), 6.97 (1H, m), 6.92 (2H, m), 6.61 (1H, d), 4.24 (2H, t), 4.15 (2H, q), 3,74 (2H, m), 2.57 (2H, t), 2.13 (2H, m), 1.98 (2H, m), 1.62 (4H, m), 1.39 (2H, m), 1.26 (3H, t)[2516] <1>H-NMR (CDCl<3>) δ 7.16 (1H, m), 6.97 (1H, m), 6.92 (2H, m), 6.61 (1H, d), 4.24 (2H, t), 4.15 (2H, q), 3.74 (2H, m), 2.57 (2H, t), 2.13 (2H, m), 1.98 (2H, m), 1.62 (4H, m), 1.39 (2H, m), 1.26 (3H, t)

[2518] Faza B: 4-[4-[5-hloro-2-(ciklopentilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina[2518] Phase B: 4-[4-[5-chloro-2-(cyclopentylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid

[2519] Etil 4-[4-[5-hloro-2-(ciklopentilamino)fenil]-2,6-difluoro-fenoksi] butanoat (0.1 g, 0.23 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.059 g, 63%).[2519] Ethyl 4-[4-[5-chloro-2-(cyclopentylamino)phenyl]-2,6-difluoro-phenoxy]butanoate (0.1 g, 0.23 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.059 g, 63%).

[2520] <1>H-NMR (CDCl<3>) δ 7.15 (1H, m), 6.98 (1H, m), 6.92 (2H, m), 6.62 (1H, d), 4.25 (2H, t), 3.73 (1H, m), 2.67 (2H, t), 2.13 (2H, m), 1.92 (2H, m), 1.64 (4H, m), 1.38 (2H, m)[2520] <1>H-NMR (CDCl<3>) δ 7.15 (1H, m), 6.98 (1H, m), 6.92 (2H, m), 6.62 (1H, d), 4.25 (2H, t), 3.73 (1H, m), 2.67 (2H, t), 2.13 (2H, m), 1.92 (2H, m), 1.64 (4H, m), 1.38 (2H, m)

[2522] Primer 96: 4-[4-[2-(ciklopentilamino)-5-fluoro-fenil]-2,6-difluoro-fenoksi]buterna kiselina[2522] Example 96: 4-[4-[2-(cyclopentylamino)-5-fluoro-phenyl]-2,6-difluoro-phenoxy]butyric acid

[2523][2523]

[2525] [2525]

[2528] Faza A: etil 4-[4-[2-(ciklopentilamino)-5-fluoro-fenil]-2,6-difluoro-fenoksi]butanoat[2528] Phase A: ethyl 4-[4-[2-(cyclopentylamino)-5-fluoro-phenyl]-2,6-difluoro-phenoxy]butanoate

[2529] N-ciklopentil-f-fluoro-2-jodo-anilin (0.055 g, 0.18 mmol) dobijen u primeru pripreme 82 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.066g, 0.18 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.053g, 70%).[2529] N-cyclopentyl-f-fluoro-2-iodo-aniline (0.055 g, 0.18 mmol) obtained in preparation example 82 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.066 g, 0.18 mmol) obtained in preparation example 2 were used to react in the same manner as in Step A of Example 28 to give the title compound (0.053g, 70%).

[2530] <1>H-NMR (CDCl<3>) δ 6.96 (3H, m), 6.77 (1H, m), 6.63 (1H, m), 4.23 (2H, t), 4.15 (2H, q), 3.72 (1H, m), 3.60 (1H, brs), 2.59 (2H, t), 2.11 (2H, m), 1.96 (2H, m), 1.64 (4H, m), 1.38 (2H, m), 1.27 (3H, t)[2530] <1>H-NMR (CDCl<3>) δ 6.96 (3H, m), 6.77 (1H, m), 6.63 (1H, m), 4.23 (2H, t), 4.15 (2H, q), 3.72 (1H, m), 3.60 (1H, brs), 2.59 (2H, t), 2.11 (2H, m), 1.96 (2H, m), 1.64 (4H, m), 1.38 (2H, m), 1.27 (3H, t)

[2532] Faza B: 4-[4-[2-(ciklopentilamino)-5-fluoro-fenil]-2,6-difluoro-fenoksi] buterna kiselina[2532] Phase B: 4-[4-[2-(cyclopentylamino)-5-fluoro-phenyl]-2,6-difluoro-phenoxy] butyric acid

[2533] Etil 4-[4-[2-(ciklopentilamino)-5-fluoro-fenil]-2,6-difluoro-fenoksi] butanoat (0.053 g, 0.125 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.004 g, 8%).[2533] Ethyl 4-[4-[2-(cyclopentylamino)-5-fluoro-phenyl]-2,6-difluoro-phenoxy] butanoate (0.053 g, 0.125 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.004 g, 8%).

[2534] <1>H-NMR (CDCl<3>) δ 6.96 (3H, m), 6.76 (1H, m), 6.64 (1H, m), 4.25 (2H, t), 3.71 (1H, m), 2.68 (2H, t), 2.13 (2H, m), 1.99 (2H, m), 1.62 (4H, m), 1.38 (2H, m)[2534] <1>H-NMR (CDCl<3>) δ 6.96 (3H, m), 6.76 (1H, m), 6.64 (1H, m), 4.25 (2H, t), 3.71 (1H, m), 2.68 (2H, t), 2.13 (2H, m), 1.99 (2H, m), 1.62 (4H, m), 1.38 (2H, m)

[2536] Primer 97: 4-[4-(3-ciklopentilfenil)-2,6-difluoro-fenoksi]buterna kiselina[2536] Example 97: 4-[4-(3-cyclopentylphenyl)-2,6-difluoro-phenoxy]butyric acid

[2537][2537]

[2539] [2539]

[2542] 1-ciklopentil-3-jodo-benzen (0.045 g, 0.16 mmol)dobijen u primeru pripreme 86 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.061 g, 0.16 mmol) dobijen u primeru pripreme 2 su korišćeni da bi sekvencijalno reagovali na isti način kao u fazi A primera 29 i fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.017 g, 30%).[2542] 1-Cyclopentyl-3-iodo-benzene (0.045 g, 0.16 mmol) obtained in Preparation Example 86 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.061 g, 0.16 mmol) obtained in Preparation Example 2 were used to reacted sequentially in the same manner as in Phase A of Example 29 and Phase B of Example 1 to give the title compound (0.017 g, 30%).

[2543] <1>H-NMR (CDCl<3>) δ 7.36 (2H, m), 7.30 (1H, m), 7.26 (1H, m), 7.12 (2H, m), 4.23 (2H, t), 3.04 (1H, m), 2.67 (2H, t), 2.11 (4H, m), 1.83 (2H, m), 1.72 (2H, m), 1.62 (2H, m)[2543] <1>H-NMR (CDCl<3>) δ 7.36 (2H, m), 7.30 (1H, m), 7.26 (1H, m), 7.12 (2H, m), 4.23 (2H, t), 3.04 (1H, m), 2.67 (2H, t), 2.11 (4H, m), 1.83 (2H, m), 1.72 (2H, m), 1.62 (2H, m)

[2545] Primer 98: 4-[4-[3-(ciklopentilmetil)fenil]-2,6-difluoro-fenoksi]buterna kiselina[2545] Example 98: 4-[4-[3-(cyclopentylmethyl)phenyl]-2,6-difluoro-phenoxy]butyric acid

[2546][2546]

[2548] [2548]

[2551] Faza A: etil 4-[4-[3-(ciklopentilmetil)fenil]-2,6-difluoro-fenoksi]butanoat[2551] Phase A: ethyl 4-[4-[3-(cyclopentylmethyl)phenyl]-2,6-difluoro-phenoxy]butanoate

[2552] 1-bromo-3-(ciklopentilmetil)benzen (0.115 g, 0.48 mmol) dobijen u primeru pripreme 87 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.118 g, 0.32 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.08 g, 62%).[2552] 1-Bromo-3-(cyclopentylmethyl)benzene (0.115 g, 0.48 mmol) obtained in Preparation Example 87 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.118 g, 0.32 mmol) obtained in Preparation Example 2 were used to reacted in the same manner as in Step A of Example 29 to give the title compound (0.08 g, 62%).

[2553] <1>H-NMR (CDCl<3>) δ 7.31 (3H, m), 7.15 (1H, d), 7.11 (2H, m), 4.21 (2H, t), 4.15 (2H, q), 2.66 (2H, d), 2.58 (2H, t), 2.10 (3H, m), 1.72 (2H, m), 1.65 (2H, m), 1.52 (2H, m), 1.27 (3H, t), 1.20 (2H, m)[2553] <1>H-NMR (CDCl<3>) δ 7.31 (3H, m), 7.15 (1H, d), 7.11 (2H, m), 4.21 (2H, t), 4.15 (2H, q), 2.66 (2H, d), 2.58 (2H, t), 2.10 (3H, m), 1.72 (2H, m), 1.65 (2H, m), 1.52 (2H, m), 1.27 (3H, t), 1.20 (2H, m)

[2555] Faza B: 4-[4-[3-(ciklopentilmetil)fenil]-2,6-difluoro-fenoksi]buterna kiselina[2555] Phase B: 4-[4-[3-(cyclopentylmethyl)phenyl]-2,6-difluoro-phenoxy]butyric acid

[2556] Etil 4-[4-[3-(ciklopentilmetil)fenil]-2,6-difluoro-fenoksi]butanoat (0.08 g, 0.2 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.07 g, 94%).[2556] Ethyl 4-[4-[3-(cyclopentylmethyl)phenyl]-2,6-difluoro-phenoxy]butanoate (0.08 g, 0.2 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.07 g, 94%).

[2557] <1>H-NMR (CDCl<3>) δ 7.31 (3H, m), 7.17 (1H, m), 7.11 (2H, m), 4.22 (2H, t), 2.67 (4H, m), 2.11 (3H, m), 1.72 (2H, m), 1.65 (2H, m), 1.53 (2H, m), 1.22 (2H, m)[2557] <1>H-NMR (CDCl<3>) δ 7.31 (3H, m), 7.17 (1H, m), 7.11 (2H, m), 4.22 (2H, t), 2.67 (4H, m), 2.11 (3H, m), 1.72 (2H, m), 1.65 (2H, m), 1.53 (2H, m), 1.22 (2H, m)

[2559] Primer 99: 4-[4-[2-(ciklopentilmetil)fenil]-2,6-difluoro-fenoksi] buterna kiselina[2559] Example 99: 4-[4-[2-(cyclopentylmethyl)phenyl]-2,6-difluoro-phenoxy]butyric acid

[2560][2560]

[2562] [2562]

[2565] Faza A: etil 4-[4-[2-(ciklopentilmetil)fenil]-2,6-difluoro-fenoksi]butanoat[2565] Phase A: ethyl 4-[4-[2-(cyclopentylmethyl)phenyl]-2,6-difluoro-phenoxy]butanoate

[2566] 1-bromo-2-(ciklopentilmetil)benzen (0.24 g, 1 mmol) dobijen u primeru pripreme 88 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.24 g, 0.66 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.13 g, 49%).[2566] 1-Bromo-2-(cyclopentylmethyl)benzene (0.24 g, 1 mmol) obtained in Preparation Example 88 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.24 g, 0.66 mmol) obtained in Preparation Example 2 were used to react in the same manner. as in Step A of Example 28 to give the title compound (0.13 g, 49%).

[2567] <1>H-NMR (CDCl<3>) δ 7.29 (2H, m), 7.21 (1H, m), 7.12 (1H, d), 6.84 (2H, m), 4.22 (2H, t), 4.17 (2H, q), 2.60 (4H, m), 2.12 (2H, m), 1.89 (1H, m), 1.58 (4H, m), 1.43 (2H, m), 1.28 (3H, t), 1.02 (2H, m)[2567] <1>H-NMR (CDCl<3>) δ 7.29 (2H, m), 7.21 (1H, m), 7.12 (1H, d), 6.84 (2H, m), 4.22 (2H, t), 4.17 (2H, q), 2.60 (4H, m), 2.12 (2H, m), 1.89 (1H, m), 1.58 (4H, m), 1.43 (2H, m), 1.28 (3H, t), 1.02 (2H, m)

[2569] Faza B: 4-[4-[2-(ciklopentilmetil)fenil]-2.6-difluoro-fenoksi]buterna kiselina[2569] Phase B: 4-[4-[2-(cyclopentylmethyl)phenyl]-2,6-difluoro-phenoxy]butyric acid

[2570] Etil 4-[4-[2-(ciklopentilmetil)fenil]-2,6-difluoro-fenoksi]butanoat (0.13 g, 0.32 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.1 g, 83%).[2570] Ethyl 4-[4-[2-(cyclopentylmethyl)phenyl]-2,6-difluoro-phenoxy]butanoate (0.13 g, 0.32 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.1 g, 83%).

[2571] <1>H-NMR (CDCl<3>) δ 7.28 (2H, m), 7.21 (1H, m), 7.12 (1H, d), 6.82 (2H, m), 4.24 (2H, t), 2.68 (2H, t), 2.59 (2H, d), 2.14 (2H, m), 1.90 (1H, m), 1.57 (2H, m), 1.52 (2H, m), 1.43 (2H, m), 1.02 (2H, m)[2571] <1>H-NMR (CDCl<3>) δ 7.28 (2H, m), 7.21 (1H, m), 7.12 (1H, d), 6.82 (2H, m), 4.24 (2H, t), 2.68 (2H, t), 2.59 (2H, d), 2.14 (2H, m), 1.90 (1H, m), 1.57 (2H, m), 1.52 (2H, m), 1.43 (2H, m), 1.02 (2H, m)

[2572] Primer 100: 4-[4-[6-(ciklopentilmetil)-2-piridil]-2,6-difluoro-fenoksi] buterna kiselina[2572] Example 100: 4-[4-[6-(cyclopentylmethyl)-2-pyridyl]-2,6-difluoro-phenoxy] butyric acid

[2573][2573]

[2575] [2575]

[2578] Faza A: etil 4-[4-[6-(ciklopentilidenmetil)-2-piridil]-2,6-difluoro-fenoksi] butanoat[2578] Phase A: Ethyl 4-[4-[6-(cyclopentylidenemethyl)-2-pyridyl]-2,6-difluoro-phenoxy] butanoate

[2579] 2-bromo-6-(ciklopentilidenmetil)piridin (0.13 g, 0.54 mmol) dobijen u primeru pripreme 91 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.155 g, 0.42 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.15 g, 89%).[2579] 2-Bromo-6-(cyclopentylidenemethyl)pyridine (0.13 g, 0.54 mmol) obtained in Preparation Example 91 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.155 g, 0.42 mmol) obtained in Preparation Example 2 were used to reacted in the same manner as in Step A of Example 29 to give the title compound (0.15 g, 89%).

[2580] <1>H-NMR (CDCl<3>) δ 7.63 (3H, m), 7.39 (1H, d), 7.12 (1H, d), 6.50 (1H, m), 4.23 (2H, t), 4.16 (2H, q), 2.88 (2H, m), 2.57 (4H, m), 2.10 (2H, m), 1.84 (2H, m), 1.71 (2H, m), 1.27 (3H, t)[2580] <1>H-NMR (CDCl<3>) δ 7.63 (3H, m), 7.39 (1H, d), 7.12 (1H, d), 6.50 (1H, m), 4.23 (2H, t), 4.16 (2H, q), 2.88 (2H, m), 2.57 (4H, m), 2.10 (2H, m), 1.84 (2H, m), 1.71 (2H, m), 1.27 (3H, t)

[2582] Faza B: etil 4-[4-[6-(ciklopentilmetil)-2-piridil]-2,6-difluoro-fenoksi] butanoat[2582] Phase B: Ethyl 4-[4-[6-(cyclopentylmethyl)-2-pyridyl]-2,6-difluoro-phenoxy] butanoate

[2583] Etil 4-[4-[6-(ciklopentilidenmetil)-2-piridil]-2,6-difluoro-fenoksi] butanoat (0.15 g, 0.37 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera pripreme 50 da bi se dobilo naslovno jedinjenje (0.15 g, 99%).[2583] Ethyl 4-[4-[6-(cyclopentylidenemethyl)-2-pyridyl]-2,6-difluoro-phenoxy] butanoate (0.15 g, 0.37 mmol) obtained in Step A was used to react in the same manner as in Step B of Preparation Example 50 to give the title compound (0.15 g, 99%).

[2584] <1>H-NMR (CDCl<3>) δ 7.63 (1H, t), 7.59 (2H, m), 7.43 (1H, d), 7.07 (1H, t), 4.21 (2H, t), 4.14 (2H, q), 2.82 (2H, d), 2.58 (2H, t), 2.34 (1H, m), 2.10 (2H, m), 1.65 (8H, m), 1.27 (3H, t)[2584] <1>H-NMR (CDCl<3>) δ 7.63 (1H, t), 7.59 (2H, m), 7.43 (1H, d), 7.07 (1H, t), 4.21 (2H, t), 4.14 (2H, q), 2.82 (2H, d), 2.58 (2H, t), 2.34 (1H, m), 2.10 (2H, m), 1.65 (8H, m), 1.27 (3H, t)

[2586] Faza C: 4-[4-[6-(ciklopentilmetil)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina[2586] Phase C: 4-[4-[6-(cyclopentylmethyl)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid

[2587] Etil 4-[4-[6-(ciklopentilmetil)-2-piridil]-2,6-difluoro-fenoksi]butanoat (0.15 g, 0.37 mmol) dobijen u fazi B je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.106 g, 76%).[2587] Ethyl 4-[4-[6-(cyclopentylmethyl)-2-pyridyl]-2,6-difluoro-phenoxy]butanoate (0.15 g, 0.37 mmol) obtained in Step B was used to react in the same manner as in Step B of Example 1 to give the title compound (0.106 g, 76%).

[2588] <1>H-NMR (CDCl<3>) δ 7.63 (1H, t), 7.57 (2H, m), 7.43 (1H, d), 7.07 (1H, d), 4.23 (2H, t), 2.82 (2H, d), 2.66 (2H, t), 2.34 (1H, m), 2.12 (2H, m), 1.74 (2H, m), 1.66 (2H, m), 1.54 (2H, m), 1.27 (2H, m)[2588] <1>H-NMR (CDCl<3>) δ 7.63 (1H, t), 7.57 (2H, m), 7.43 (1H, d), 7.07 (1H, d), 4.23 (2H, t), 2.82 (2H, d), 2.66 (2H, t), 2.34 (1H, m), 2.12 (2H, m), 1.74 (2H, m), 1.66 (2H, m), 1.54 (2H, m), 1.27 (2H, m)

[2590] Primer 101: 4-[4-[2-(ciklobutilmetil)fenil]-2,6-difluoro-fenoksi] buterna kiselina[2590] Example 101: 4-[4-[2-(cyclobutylmethyl)phenyl]-2,6-difluoro-phenoxy] butyric acid

[2591][2591]

[2593] [2593]

[2594] Faza A: etil 4-[4-[2-(ciklobutilmetil)fenil]-2,6-difluoro-fenoksi]butanoat[2594] Phase A: Ethyl 4-[4-[2-(cyclobutylmethyl)phenyl]-2,6-difluoro-phenoxy]butanoate

[2595] 1-bromo-2-(ciklobutilmetil)benzen (0.06 g, 0.26 mmol) dobijen u primeru pripreme 92 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.08 g, 0.21 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.035 g, 43%).[2595] 1-Bromo-2-(cyclobutylmethyl)benzene (0.06 g, 0.26 mmol) obtained in Preparation Example 92 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.08 g, 0.21 mmol) obtained in Preparation Example 2 were used to react with the same way as in step A of Example 28 to give the title compound (0.035 g, 43%).

[2596] <1>H-NMR (CDCl<3>) δ 7.28 (1H, m), 7.21 (2H, m), 7.12 (1H, m), 6.82 (2H, m), 4.23 (2H, t), 4.16 (2H, q), 2.66 (2H, d), 2.60 (2H, t), 2.41 (1H, m), 2.13 (2H, m), 1.95 (2H, m), 1.76 (2H, m), 1.57 (2H, m), 1.27 (3H, t)[2596] <1>H-NMR (CDCl<3>) δ 7.28 (1H, m), 7.21 (2H, m), 7.12 (1H, m), 6.82 (2H, m), 4.23 (2H, t), 4.16 (2H, q), 2.66 (2H, d), 2.60 (2H, t), 2.41 (1H, m), 2.13 (2H, m), 1.95 (2H, m), 1.76 (2H, m), 1.57 (2H, m), 1.27 (3H, t)

[2598] Faza B: 4-[4-[2-(ciklobutilmetil)fenil]-2,6-difluoro-fenoksi]buterna kiselina[2598] Phase B: 4-[4-[2-(cyclobutylmethyl)phenyl]-2,6-difluoro-phenoxy]butyric acid

[2599] Etil 4-[4-[2-(ciklobutilmetil)fenil]-2,6-difluoro-fenoksi]butanoat (0.035 g, 0.09 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.02 g, 61%).[2599] Ethyl 4-[4-[2-(cyclobutylmethyl)phenyl]-2,6-difluoro-phenoxy]butanoate (0.035 g, 0.09 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.02 g, 61%).

[2600] <1>H-NMR (CDCl<3>) δ 7.78 (1H, m), 7.21 (2H, m), 7.12 (1H, m), 6.84 (2H, m), 4.24 (2H, t), 2.67 (4H, m), 2.41 (1H, m), 2.13 (2H, m), 1.95 (2H, m), 1.75 (2H, m), 1.57 (2H, m)[2600] <1>H-NMR (CDCl<3>) δ 7.78 (1H, m), 7.21 (2H, m), 7.12 (1H, m), 6.84 (2H, m), 4.24 (2H, t), 2.67 (4H, m), 2.41 (1H, m), 2.13 (2H, m), 1.95 (2H, m), 1.75 (2H, m), 1.57 (2H, m)

[2602] Primer 102: 4-[4-[3-(ciklobutilmetil)fenil]-2,6-difluoro-fenoksi]buterna kiselina[2602] Example 102: 4-[4-[3-(cyclobutylmethyl)phenyl]-2,6-difluoro-phenoxy]butyric acid

[2603][2603]

[2605] [2605]

[2608] Faza A: etil 4-[4-[3-(ciklobutilmetil)fenil]-2,6-difluoro-fenoksi]butanoat[2608] Phase A: ethyl 4-[4-[3-(cyclobutylmethyl)phenyl]-2,6-difluoro-phenoxy]butanoate

[2609] 1-bromo-3-(ciklobutilmetil)benzen (0.03 g, 0.13 mmol) dobijen u primeru pripreme 93 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.041 g, 0.11 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.012 g, 28%).[2609] 1-Bromo-3-(cyclobutylmethyl)benzene (0.03 g, 0.13 mmol) obtained in Preparation Example 93 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.041 g, 0.11 mmol) obtained in Preparation Example 2 were used to react in the same manner as in Step A of Example 29 to give the title compound (0.012 g, 28%).

[2610] <1>H-NMR (CDCl<3>) δ 7.32 (3H, m), 7.10 (3H, m), 4.21 (2H, t), 4.15 (2H, q), 2.75 (2H, d), 2.59 (3H, m), 2.10 (4H, m), 1.85 (2H, m), 1.74 (2H, m), 1.27 (3H, t)[2610] <1>H-NMR (CDCl<3>) δ 7.32 (3H, m), 7.10 (3H, m), 4.21 (2H, t), 4.15 (2H, q), 2.75 (2H, d), 2.59 (3H, m), 2.10 (4H, m), 1.85 (2H, m), 1.74 (2H, m), 1.27 (3H, t)

[2612] Faza B: 4-[4-[3-(ciklobutilmetil)fenil]-2,6-difluoro-fenoksilbuterna kiselina[2612] Phase B: 4-[4-[3-(cyclobutylmethyl)phenyl]-2,6-difluoro-phenoxybutyric acid

[2613] Etil 4-[4-[3-(ciklobutilmetil)fenil]-2,6-difluoro-fenoksi]butanoat (0.012 g, 0.03 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.01 g, 92%).[2613] Ethyl 4-[4-[3-(cyclobutylmethyl)phenyl]-2,6-difluoro-phenoxy]butanoate (0.012 g, 0.03 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.01 g, 92%).

[2614] 1H-NMR (MeOH-d<4>) δ 7.34 (3H, m), 7.22 (2H, m), 7.16 (1H, m), 4.19 (2H, t), 2.75 (2H, d), 2.61 (1H, m), 2.56 (2H, t), 2.06 (4H, m), 1.85 (2H, m), 1.76 (2H, m)[2614] 1H-NMR (MeOH-d<4>) δ 7.34 (3H, m), 7.22 (2H, m), 7.16 (1H, m), 4.19 (2H, t), 2.75 (2H, d), 2.61 (1H, m), 2.56 (2H, t), 2.06 (4H, m), 1.85 (2H, m), 1.76 (2H, m)

[2615] Primer 103: 4-[4-[6-(ciklobutilmetil)-2-piridil]-2,6-difluoro-fenoksi] buterna kiselina[2615] Example 103: 4-[4-[6-(cyclobutylmethyl)-2-pyridyl]-2,6-difluoro-phenoxy] butyric acid

[2616][2616]

[2618] [2618]

[2621] Faza A: etil 4-[4-[6-(ciklobutilidenmetil)-2-piridil]-2,6-difluoro-fenoksi] butanoat[2621] Phase A: ethyl 4-[4-[6-(cyclobutylidenemethyl)-2-pyridyl]-2,6-difluoro-phenoxy] butanoate

[2622] 2-bromo-6-(ciklobutilidenmetil)piridin (0.096 g, 0.43 mmol) dobijen u primeru pripreme 94 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.105 g, 0.28 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.085 g, 75%).[2622] 2-Bromo-6-(cyclobutylidenemethyl)pyridine (0.096 g, 0.43 mmol) obtained in Preparation Example 94 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.105 g, 0.28 mmol) obtained in Preparation Example 2 were used to reacted in the same manner as in Step A of Example 29 to give the title compound (0.085 g, 75%).

[2623] <1>H-NMR (CDCl<3>) δ 7.64 (1H, t), 7.60 (2H, m), 7.38 (1H, d), 7.04 (1H, d), 6.27 (1H, m), 4.23 (2H, t), 4.17 (2H, q), 3.27 (2H, m), 2.94 (2H, m), 2.59 (2H, t), 2.18 (2H, m), 2.10 (2H, m), 1.27 (3H, t)[2623] <1>H-NMR (CDCl<3>) δ 7.64 (1H, t), 7.60 (2H, m), 7.38 (1H, d), 7.04 (1H, d), 6.27 (1H, m), 4.23 (2H, t), 4.17 (2H, q), 3.27 (2H, m), 2.94 (2H, m), 2.59 (2H, t), 2.18 (2H, m), 2.10 (2H, m), 1.27 (3H, t)

[2625] Faza B: etil 4-[4-[6-(ciklobutilmetil)-2-piridil]-2,6-difluoro-fenoksi]butanoat[2625] Phase B: ethyl 4-[4-[6-(cyclobutylmethyl)-2-pyridyl]-2,6-difluoro-phenoxy]butanoate

[2626] Etil 4-[4-[6-(ciklobutilidenmetil)-2-piridil]-2,6-difluoro-fenoksi] butanoat (0.085 g, 0.22 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera pripreme 50 da bi se dobilo naslovno jedinjenje (0.082 g, 95%).[2626] Ethyl 4-[4-[6-(cyclobutylidenemethyl)-2-pyridyl]-2,6-difluoro-phenoxy] butanoate (0.085 g, 0.22 mmol) obtained in Step A was used to react in the same manner as in Step B of Preparation Example 50 to give the title compound (0.082 g, 95%).

[2627] <1>H-NMR (CDCl<3>) δ 7.62 (1H, t), 7.57 (2H, m), 7.42 (1H, d), 7.04 (1H, d), 4.22 (2H, t), 2.16 (2H, q), 2.92 (2H, d), 2.79 (1H, m), 2.57 (2H, t), 2.10 (4H, m), 1.88 (2H, m), 1.80 (2H, m), 1.27 (3H, t)[2627] <1>H-NMR (CDCl<3>) δ 7.62 (1H, t), 7.57 (2H, m), 7.42 (1H, d), 7.04 (1H, d), 4.22 (2H, t), 2.16 (2H, q), 2.92 (2H, d), 2.79 (1H, m), 2.57 (2H, t), 2.10 (4H, m), 1.88 (2H, m), 1.80 (2H, m), 1.27 (3H, t)

[2629] Faza C: 4-[4-[6-(ciklobutilmetil)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina[2629] Phase C: 4-[4-[6-(cyclobutylmethyl)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid

[2630] Etil 4-[4-[6-(ciklobutilmetil)-2-piridil]-2,6-difluoro-fenoksi]butanoat (0.08 g, 0.2 mmol) dobijen u fazi B je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.075 g, 99%).[2630] Ethyl 4-[4-[6-(cyclobutylmethyl)-2-pyridyl]-2,6-difluoro-phenoxy]butanoate (0.08 g, 0.2 mmol) obtained in Step B was used to react in the same manner as in Step B of Example 1 to give the title compound (0.075 g, 99%).

[2631] <1>H-NMR (CDCl<3>) δ 7.62 (1H, t), 7.57 (2H, m), 7.42 (1H, d), 7.04 (1H, d), 4.23 (2H, t), 2.93 (2H, d), 2.78 (1H, m), 2.67 (2H, t), 2.11 (4H, m), 1.89 (2H, m), 1.80 (2H, m)[2631] <1>H-NMR (CDCl<3>) δ 7.62 (1H, t), 7.57 (2H, m), 7.42 (1H, d), 7.04 (1H, d), 4.23 (2H, t), 2.93 (2H, d), 2.78 (1H, m), 2.67 (2H, t), 2.11 (4H, m), 1.89 (2H, m), 1.80 (2H, m)

[2633] Primer 104: 4-[4-(2-ciklopentilfenil)-2,6-difluoro-fenoksi]buterna kiselina[2633] Example 104: 4-[4-(2-cyclopentylphenyl)-2,6-difluoro-phenoxy]butyric acid

[2634][2634]

[2636] [2636]

[2637] Faza A: etil 4-[4-(2-ciklopentilfenil)-2,6-difluoro-fenoksi]butanoat[2637] Phase A: ethyl 4-[4-(2-cyclopentylphenyl)-2,6-difluoro-phenoxy]butanoate

[2638] 1-ciklopentil-2-jodo-benzen (0.065 g, 0.23 mmol) dobijen u primeru pripreme 97 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.073 g, 0.2 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.036 g, 46%).[2638] 1-Cyclopentyl-2-iodo-benzene (0.065 g, 0.23 mmol) obtained in Preparation Example 97 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.073 g, 0.2 mmol) obtained in Preparation Example 2 were used to reacted in the same manner as in Step A of Example 28 to give the title compound (0.036 g, 46%).

[2639] <1>H-NMR (CDCl<3>) δ 7.37 (2H, m), 7.18 (1H, t), 7.11 (1H, d), 6.82 (2H, m), 4.22 (2H, t), 4.15 (2H, q), 3.00 (1H, m), 2.60 (2H, t), 2.12 (2H, m), 1.91 (2H, m), 1.79 (2H, m), 1.58 (4H, m), 1.27 (3H, t)[2639] <1>H-NMR (CDCl<3>) δ 7.37 (2H, m), 7.18 (1H, t), 7.11 (1H, d), 6.82 (2H, m), 4.22 (2H, t), 4.15 (2H, q), 3.00 (1H, m), 2.60 (2H, t), 2.12 (2H, m), 1.91 (2H, m), 1.79 (2H, m), 1.58 (4H, m), 1.27 (3H, t)

[2641] Faza B: 4-[4-(2-ciklopentilfenil)-2,6-difluoro-fenoksi]buterna kiselina[2641] Phase B: 4-[4-(2-cyclopentylphenyl)-2,6-difluoro-phenoxy]butyric acid

[2642] Etil 4-[4-(2-ciklopentilfenil)-2,6-difluoro-fenoksi]butanoat (0.036 g, 0.09 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.03 g, 92%).[2642] Ethyl 4-[4-(2-cyclopentylphenyl)-2,6-difluoro-phenoxy]butanoate (0.036 g, 0.09 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.03 g, 92%).

[2643] <1>H-NMR (CDCl<3>) δ 7.36 (2H, m), 7.18 (1H, t), 7.11 (1H, d), 6.82 (2H, m), 4.23 (2H, t), 2.99 (1H, m), 2.67 (2H, t), 2.14 (2H, m), 1.92 (2H, m), 1.80 (2H, m), 1.59 (4H, m)[2643] <1>H-NMR (CDCl<3>) δ 7.36 (2H, m), 7.18 (1H, t), 7.11 (1H, d), 6.82 (2H, m), 4.23 (2H, t), 2.99 (1H, m), 2.67 (2H, t), 2.14 (2H, m), 1.92 (2H, m), 1.80 (2H, m), 1.59 (4H, m)

[2645] Primer 105: 4-[4-(6-ciklopentil-2-piridil)-2,6-difluoro-fenoksi]buterna kiselina[2645] Example 105: 4-[4-(6-cyclopentyl-2-pyridyl)-2,6-difluoro-phenoxy]butyric acid

[2646][2646]

[2648] [2648]

[2651] Faza A: etil 4-[4-(6-ciklopentil-2-piridil)-2,6-difluoro-fenoksi]butanoat[2651] Phase A: ethyl 4-[4-(6-cyclopentyl-2-pyridyl)-2,6-difluoro-phenoxy]butanoate

[2652] 2-bromo-6-ciklopentil-piridin (0.1 g, 0.44 mmol) dobijen u primeru pripreme 98 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.125 g, 0.34 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.091 g, 68%).[2652] 2-Bromo-6-cyclopentyl-pyridine (0.1 g, 0.44 mmol) obtained in Preparation Example 98 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.125 g, 0.34 mmol) obtained in Preparation Example 2 were used to react in the same manner as in Step A of Example 29 to give the title compound (0.091 g, 68%).

[2653] <1>H-NMR (CDCl<3>) δ 7.60 (3H, m), 7.43 (1H, d), 7.10 (1H, d), 4.20 (2H, t), 4.14 (2H, q), 3.21 (1H, m), 2.56 (2H, t), 2.09 (4H, m), 1.86 (4H, m), 1.72 (2H, m), 1.26 (3H, t)[2653] <1>H-NMR (CDCl<3>) δ 7.60 (3H, m), 7.43 (1H, d), 7.10 (1H, d), 4.20 (2H, t), 4.14 (2H, q), 3.21 (1H, m), 2.56 (2H, t), 2.09 (4H, m), 1.86 (4H, m), 1.72 (2H, m), 1.26 (3H, t)

[2655] Faza B: 4-[4-(6-ciklopentil-2-piridil)-2,6-difluoro-fenoksi]buterna kiselina[2655] Phase B: 4-[4-(6-cyclopentyl-2-pyridyl)-2,6-difluoro-phenoxy]butyric acid

[2656] Etil 4-[4-(6-ciklopentil-2-piridil)-2,6-difluoro-fenoksi]butanoat (0.09 g, 0.23 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.07 g, 84%).[2656] Ethyl 4-[4-(6-cyclopentyl-2-pyridyl)-2,6-difluoro-phenoxy]butanoate (0.09 g, 0.23 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.07 g, 84%).

[2657] <1>H-NMR (CDCl<3>) δ 7.62 (3H, m), 7.42 (1H, d), 7.11 (1H, d), 4.23 (2H, t), 3.22 (1H, m), 2.67 (2H, t), 2.12 (4H, m), 1.86 (4H, m), 1.71 (2H, m)[2657] <1>H-NMR (CDCl<3>) δ 7.62 (3H, m), 7.42 (1H, d), 7.11 (1H, d), 4.23 (2H, t), 3.22 (1H, m), 2.67 (2H, t), 2.12 (4H, m), 1.86 (4H, m), 1.71 (2H, m)

[2658] Primer 106: 4-[2,6-difluoro-4-(2-izobutil-3-piridil)fenoksi]buterna kiselina[2658] Example 106: 4-[2,6-difluoro-4-(2-isobutyl-3-pyridyl)phenoxy]butyric acid

[2659][2659]

[2661] [2661]

[2664] Faza A: etil 4-[2,6-difluoro-4-(2-izobutil-3-piridil)fenoksi]butanoat[2664] Phase A: Ethyl 4-[2,6-difluoro-4-(2-isobutyl-3-pyridyl)phenoxy]butanoate

[2665] (2-izobutil-3-piridil) trifluorometansulfonat (0.017 g, 0.06 mmol) dobijen u primeru pripreme 103 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.026 g, 0.07 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.013 g, 57%).[2665] (2-isobutyl-3-pyridyl) trifluoromethanesulfonate (0.017 g, 0.06 mmol) obtained in preparation example 103 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.026 g, 0.07 mmol) obtained in preparation example 2 were used to react in the same manner as in Step A of Example 29 to give the title compound (0.013 g, 57%).

[2666] <1>H-NMR (CDCl<3>) δ 8.57 (1H, m), 7.44 (1H, m), 7.16 (1H, m), 6.83 (2H, m), 4.26 (2H, t), 4.16 (2H, q), 2.65 (2H, d), 2.61 (2H, t), 2.13 (3H, m), 1.26 (3H, t), 0.80 (6H, d)[2666] <1>H-NMR (CDCl<3>) δ 8.57 (1H, m), 7.44 (1H, m), 7.16 (1H, m), 6.83 (2H, m), 4.26 (2H, t), 4.16 (2H, q), 2.65 (2H, d), 2.61 (2H, t), 2.13 (3H, m), 1.26 (3H, t), 0.80 (6H, d)

[2668] Faza B: 4-[2,6-difluoro-4-(2-izobutil-3-piridil)fenoksi]buterna kiselina[2668] Phase B: 4-[2,6-difluoro-4-(2-isobutyl-3-pyridyl)phenoxy]butyric acid

[2669] Etil 4-[2,6-difluoro-4-(2-izobutil-3-piridil)fenoksi]butanoat (0.013 g, 0.034 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje(0.004 g, 32%).[2669] Ethyl 4-[2,6-difluoro-4-(2-isobutyl-3-pyridyl)phenoxy]butanoate (0.013 g, 0.034 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.004 g, 32%).

[2670] <1>H-NMR (CDCl<3>) δ 8.60 (1H, m), 7.42 (1H, m), 7.20 (1H, m), 6.82 (2H, m), 4.27 (2H, t), 2.67 (4H, m), 2.15 (2H, m), 2.05 (1H, m), 0.78 (6H, d)[2670] <1>H-NMR (CDCl<3>) δ 8.60 (1H, m), 7.42 (1H, m), 7.20 (1H, m), 6.82 (2H, m), 4.27 (2H, t), 2.67 (4H, m), 2.15 (2H, m), 2.05 (1H, m), 0.78 (6H, d)

[2672] Primer 107: 4-[4-(2-ciklopentil-3-piridil)-2,6-difluoro-fenoksi]buterna kiselina[2672] Example 107: 4-[4-(2-cyclopentyl-3-pyridyl)-2,6-difluoro-phenoxy]butyric acid

[2673][2673]

[2675] [2675]

[2678] Faza A: etil 4-[4-(2-ciklopentil-3-piridil)-2,6-difluoro-fenoksi]butanoat[2678] Phase A: ethyl 4-[4-(2-cyclopentyl-3-pyridyl)-2,6-difluoro-phenoxy]butanoate

[2679] (2-ciklopentil-3-piridil) trifluorometansulfonat (0.376 g, 1.27 mmol) dobijen u primeru pripreme 106 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.51 g, 1.4 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.284 g, 57%).[2679] (2-Cyclopentyl-3-pyridyl) trifluoromethanesulfonate (0.376 g, 1.27 mmol) obtained in Preparation Example 106 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.51 g, 1.4 mmol) obtained in Preparation Example 2 were used to react in the same manner as in Step A of Example 29 to give the title compound (0.284 g, 57%).

[2680] <1>H-NMR (CDCl<3>) δ 8.60 (1H, m), 7.41 (1H, m), 7.12 (1H, m), 6.83 (2H, m), 4.24 (2H, t), 4.16 (2H, q), 3.16 (1H, m), 2.60 (2H, t), 2.12 (2H, m), 1.87 (6H, m), 1.59 (2H, m), 1.27 (3H, t)[2680] <1>H-NMR (CDCl<3>) δ 8.60 (1H, m), 7.41 (1H, m), 7.12 (1H, m), 6.83 (2H, m), 4.24 (2H, t), 4.16 (2H, q), 3.16 (1H, m), 2.60 (2H, t), 2.12 (2H, m), 1.87 (6H, m), 1.59 (2H, m), 1.27 (3H, t)

[2681] Faza B: 4-[4-(2-ciklopentil-3-piridil)-2,6-difluoro-fenoksi]buterna kiselina[2681] Phase B: 4-[4-(2-cyclopentyl-3-pyridyl)-2,6-difluoro-phenoxy]butyric acid

[2682] Etil 4-[4-(2-ciklopentil-3-piridil)-2,6-difluoro-fenoksi]butanoat (0.18 g, 0.46 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.15 g, 90%).[2682] Ethyl 4-[4-(2-cyclopentyl-3-pyridyl)-2,6-difluoro-phenoxy]butanoate (0.18 g, 0.46 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.15 g, 90%).

[2683] <1>H-NMR (CDCl<3>) δ 8.62 (1H, m), 7.41 (1H, m), 7.14 (1H, m), 6.84 (2H, m), 4.27 (2H, t), 3.16 (1H, m), 2.69 (2H, t), 2.14 (2H, m), 1.89 (6H, m), 1.60 (2H, m)[2683] <1>H-NMR (CDCl<3>) δ 8.62 (1H, m), 7.41 (1H, m), 7.14 (1H, m), 6.84 (2H, m), 4.27 (2H, t), 3.16 (1H, m), 2.69 (2H, t), 2.14 (2H, m), 1.89 (6H, m), 1.60 (2H, m)

[2685] Primer 108: 4-[4-[2-(ciklopentilmetil)-3-piridil]-2,6-difluoro-fenoksi] buterna kiselina[2685] Example 108: 4-[4-[2-(cyclopentylmethyl)-3-pyridyl]-2,6-difluoro-phenoxy] butyric acid

[2686][2686]

[2688] [2688]

[2691] Faza A: etil 4-[4-[2-(ciklopentilmetil)-3-piridil]-2,6-difluoro-fenoksi] butanoat[2691] Phase A: ethyl 4-[4-[2-(cyclopentylmethyl)-3-pyridyl]-2,6-difluoro-phenoxy] butanoate

[2692] [2-(ciklopentilmetil)-3-piridil] trifluorometansulfonat (0.04 g, 0.13 mmol) dobijen u primeru pripreme 108 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.052 g, 0.14 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.037 g, 70%).[2692] [2-(Cyclopentylmethyl)-3-pyridyl] trifluoromethanesulfonate (0.04 g, 0.13 mmol) obtained in Preparation Example 108 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.052 g, 0.14 mmol) obtained in Preparation Example 108 2 were used to react in the same manner as in Step A of Example 29 to give the title compound (0.037 g, 70%).

[2693] <1>H-NMR (CDCl<3>) δ 8.56 (1H, m), 7.43 (1H, m), 7.16 (1H, m), 6.82 (2H, m), 4.24 (2H, t), 4.15 (2H, q), 2.78 (2H, d), 2.60 (2H, t), 2.23 (1H, m), 2.12 (2H, m), 1.53 (6H, m), 1.27 (3H, t), 1.04 (2H, m)[2693] <1>H-NMR (CDCl<3>) δ 8.56 (1H, m), 7.43 (1H, m), 7.16 (1H, m), 6.82 (2H, m), 4.24 (2H, t), 4.15 (2H, q), 2.78 (2H, d), 2.60 (2H, t), 2.23 (1H, m), 2.12 (2H, m), 1.53 (6H, m), 1.27 (3H, t), 1.04 (2H, m)

[2695] Faza B: 4-[4-[2-(ciklopentilmetil)-3-piridil]-2,6-difluoro-fenoksi]buterna kiselina[2695] Phase B: 4-[4-[2-(cyclopentylmethyl)-3-pyridyl]-2,6-difluoro-phenoxy]butyric acid

[2696] Etil 4-[4-[2-(ciklopentilmetil)-3-piridil]-2,6-difluoro-fenoksi]butanoat (0.037 g, 0.09 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.022 g, 65%).[2696] Ethyl 4-[4-[2-(cyclopentylmethyl)-3-pyridyl]-2,6-difluoro-phenoxy]butanoate (0.037 g, 0.09 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.022 g, 65%).

[2697] <1>H-NMR (CDCl<3>) δ 8.58 (1H, m), 7.45 (1H, m), 7.17 (1H, m), 6.85 (2H, m), 4.26 (2H, t), 2.80 (2H, d), 2.67 (2H, t), 2.16 (3H, m), 1.55 (6H, m), 1.03 (2H, m)[2697] <1>H-NMR (CDCl<3>) δ 8.58 (1H, m), 7.45 (1H, m), 7.17 (1H, m), 6.85 (2H, m), 4.26 (2H, t), 2.80 (2H, d), 2.67 (2H, t), 2.16 (3H, m), 1.55 (6H, m), 1.03 (2H, m)

[2699] Primer 109: 4-[2,6-difluoro-4-(2-pirol-1-il-3-piridil)fenoksi]buterna kiselina[2699] Example 109: 4-[2,6-difluoro-4-(2-pyrrol-1-yl-3-pyridyl)phenoxy]butyric acid

[2700][2700]

[2702] [2702]

[2705] Etil 4-[2,6-difluoro-4-(2-fluoro-3-piridil)fenoksi]butanoat (0.1 g, 0.29 mmol) dobijen u primeru pripreme 109 i pirol (0.04 g, 0.59 mmol) su korišćeni da bi reagovali na isti način kao u primeru pripreme 37 da bi se dobio 2,6-difluoro-4-(2-pirol-1-il-3-piridil)fenol. Dobijeni 2,6-difluoro-4-(2-pirol-1-il-3-piridil)fenol je izreagovan sa etil estrom 4-bromo-buterne kiseline na isti način kao u primeru pripreme 12 da bi se dobio etil 4-[2,6-difluoro-4-(2-pirol-1-il-3-piridil)fenoksi]butanoat. Dobijeni etil 4-[2,6-difluoro-4-(2-pirol-1-il-3-piridil)fenoksi]butanoat je izreagovan na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.07 g, 0.07%).[2705] Ethyl 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butanoate (0.1 g, 0.29 mmol) obtained in Preparation Example 109 and pyrrole (0.04 g, 0.59 mmol) were used to react in the same manner as in Preparation Example 37 to obtain 2,6-difluoro-4-(2-pyrrol-1-yl-3-pyridyl)phenol. The resulting 2,6-difluoro-4-(2-pyrrol-1-yl-3-pyridyl)phenol was reacted with 4-bromobutyric acid ethyl ester in the same manner as in Preparation Example 12 to give ethyl 4-[2,6-difluoro-4-(2-pyrrol-1-yl-3-pyridyl)phenoxy]butanoate. The resulting ethyl 4-[2,6-difluoro-4-(2-pyrrol-1-yl-3-pyridyl)phenoxy]butanoate was reacted in the same manner as in Step B of Example 1 to give the title compound (0.07 g, 0.07%).

[2706] <1>H-NMR (CDCl<3>) δ 8.51 (1H, m), 7.71 (1H, m), 7.30 (1H, m), 6.82 (2H, m), 6.71 (2H, m), 6.19 (2H, m), 4.23 (2H, t), 2.65 (2H, t), 2.12 (2H, m)[2706] <1>H-NMR (CDCl<3>) δ 8.51 (1H, m), 7.71 (1H, m), 7.30 (1H, m), 6.82 (2H, m), 6.71 (2H, m), 6.19 (2H, m), 4.23 (2H, t), 2.65 (2H, t), 2.12 (2H, m)

[2708] Primer 110: 4-[2,6-difluoro-4-[2-(4-metilpirazol-1-il)-3-piridil] fenoksi]buterna kiselina[2708] Example 110: 4-[2,6-difluoro-4-[2-(4-methylpyrazol-1-yl)-3-pyridyl] phenoxy]butyric acid

[2709][2709]

[2711] [2711]

[2714] Faza A: etil 4-[2,6-difluoro-4-[2-(4-metilpirazol-1-il)-3-piridil]fenoksi] butanoat[2714] Phase A: ethyl 4-[2,6-difluoro-4-[2-(4-methylpyrazol-1-yl)-3-pyridyl]phenoxy] butanoate

[2715] Etil 4-[2,6-difluoro-4-(2-fluoro-3-piridil)fenoksi]butanoat (0.071 g, 0.21 mmol) dobijen u primeru pripreme 109 i 4-metilpirazol (0.021 g, 0.25 mmol) su korišćeni da bi reagovali na isti način kao u fazi A primera 72 da bi se dobilo naslovno jedinjenje (0.054 g, 64%).[2715] Ethyl 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butanoate (0.071 g, 0.21 mmol) obtained in Preparative Example 109 and 4-methylpyrazole (0.021 g, 0.25 mmol) were used to react in the same manner as in Step A of Example 72 to give the title compound (0.054 g, 64%).

[2716] <1>H-NMR (CDCl<3>) δ 8.50 (1H, m), 7.76 (1H, m), 7.70 (1H, s), 7.37 (1H, s), 7.36 (1H, m), 6.68 (2H, m), 4.20 (2H, t), 4.15 (2H, q), 2.57 (2H, t), 2.10 (5H, m), 1.27 (3H, t)[2716] <1>H-NMR (CDCl<3>) δ 8.50 (1H, m), 7.76 (1H, m), 7.70 (1H, s), 7.37 (1H, s), 7.36 (1H, m), 6.68 (2H, m), 4.20 (2H, t), 4.15 (2H, q), 2.57 (2H, t), 2.10 (5H, m), 1.27 (3H, t)

[2718] Faza B: 4-[2,6-difluoro-4-[2-(4-metilpirazol-1-il)-3-piridil]fenoksi] buterna kiselina[2718] Phase B: 4-[2,6-difluoro-4-[2-(4-methylpyrazol-1-yl)-3-pyridyl]phenoxy] butyric acid

[2719] Etil 4-[2,6-difluoro-4-[2-(4-metilpirazol-1-il)-3-piridil]fenoksi] butanoat (0.054 g, 0.13 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.016 g, 33%).[2719] Ethyl 4-[2,6-difluoro-4-[2-(4-methylpyrazol-1-yl)-3-pyridyl]phenoxy] butanoate (0.054 g, 0.13 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.016 g, 33%).

[2720] <1>H-NMR (CDCl<3>) δ 8.51 (1H, m), 7.76 (1H, m), 7.70 (1H, s), 7.38 (1H, s), 7.36 (1H, m), 6.69 (2H, m), 4.22 (2H, t), 2.64 (2H, m), 2.11 (5H, m)[2720] <1>H-NMR (CDCl<3>) δ 8.51 (1H, m), 7.76 (1H, m), 7.70 (1H, s), 7.38 (1H, s), 7.36 (1H, m), 6.69 (2H, m), 4.22 (2H, t), 2.64 (2H, m), 2.11 (5H, m)

[2722] Primer 111: 4-[2,6-difluoro-4-(2-morfolino-3-piridil)fenoksi]buterna kiselina[2722] Example 111: 4-[2,6-difluoro-4-(2-morpholino-3-pyridyl)phenoxy]butyric acid

[2723][2723]

[2725] [2725]

[2726] 4-(3-jodo-2-piridil)morfolin (0.056 g, 0.19 mmol) dobijen u primeru pripreme 110 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.072 g, 0.19 mmol) dobijen u primeru pripreme 2 su korišćeni da bi sekvencijalno reagovali na isti način kao u primeru 72 i fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.009 g, 12%).[2726] 4-(3-iodo-2-pyridyl)morpholine (0.056 g, 0.19 mmol) obtained in preparation example 110 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.072 g, 0.19 mmol) obtained in preparation example 2 were used. to react sequentially in the same manner as in Example 72 and Phase B of Example 1 to give the title compound (0.009 g, 12%).

[2727] <1>H-NMR (CDCl<3>) δ 8.26 (1H, m), 7.43 (1H, m), 7.19 (2H, m), 6.96 (1H, m), 4.25 (2H, t), 3.67 (4H, m), 3.10 (4H, m), 2.67 (2H, t), 2.12 (2H, m)[2727] <1>H-NMR (CDCl<3>) δ 8.26 (1H, m), 7.43 (1H, m), 7.19 (2H, m), 6.96 (1H, m), 4.25 (2H, t), 3.67 (4H, m), 3.10 (4H, m), 2.67 (2H, t), 2.12 (2H, m)

[2729] Primer 112: 4-[2,6-difluoro-4-[2-(tetrahidropiran-4-ilmetilamino)-3-piridil]fenoksi]butanoična kiselina [1067][2729] Example 112: 4-[2,6-difluoro-4-[2-(tetrahydropyran-4-ylmethylamino)-3-pyridyl]phenoxy]butanoic acid [1067]

[2731] [2731]

[2734] 3-jodo-N-(tetrahidropiran-4-ilmetil)piridin-2-amin (0.063 g, 0.2 mmol) dobijen u primeru pripreme 111 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.075 g, 0.2 mmol) dobijen u primeru pripreme 2 su korišćeni da bi sekvencijalno reagovali na isti način kao u primeru 72 i fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.003 g, 4%).[2734] 3-Iodo-N-(tetrahydropyran-4-ylmethyl)pyridin-2-amine (0.063 g, 0.2 mmol) obtained in Preparation Example 111 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.075 g, 0.2 mmol) obtained in Example Preparation 2 was used to react sequentially in the same manner as in Example 72 and Step B of Example 1 to give the title compound (0.003 g, 4%).

[2735] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.22 (1H, m), 6.94 (2H, m), 6.64 (1H, m), 4.57 (1H, brs), 4.28 (2H, t), 3.97 (2H, m), 3.38 (2H, m), 3.31 (2H, m), 2.67 (2H, t), 2.13 (2H, m), 1.88 (1H, m), 1.61 (2H, m), 1.34 (2H, m)[2735] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.22 (1H, m), 6.94 (2H, m), 6.64 (1H, m), 4.57 (1H, brs), 4.28 (2H, t), 3.97 (2H, m), 3.38 (2H, m), 3.31 (2H, m), 2.67 (2H, t), 2.13 (2H, m), 1.88 (1H, m), 1.61 (2H, m), 1.34 (2H, m)

[2737] Primer 113: 4-[2,6-difluoro-4-[2-(1-piperidil)-3-piridil]fenoksi] buterna kiselina[2737] Example 113: 4-[2,6-difluoro-4-[2-(1-piperidyl)-3-pyridyl]phenoxy]butyric acid

[2738][2738]

[2740] [2740]

[2743] Faza A: etil 4-[2,6-difluoro-4-[2-(1-piperidil)-3-piridil]fenoksi]butanoat[2743] Phase A: ethyl 4-[2,6-difluoro-4-[2-(1-piperidyl)-3-pyridyl]phenoxy]butanoate

[2744] Etil 4-[2,6-difluoro-4-(2-fluoro-3-piridil)fenoksi]butanoat (0.1 g, 0.29 mmol) dobijen u primeru pripreme 109, piperidin (0.05 g, 0.58 mmol) i DMSO su korišćeni da bi reagovali na isti način kao u fazi A primera 72 da bi se dobilo naslovno jedinjenje (0.022 g, 19%).[2744] Ethyl 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butanoate (0.1 g, 0.29 mmol) obtained in Preparative Example 109, piperidine (0.05 g, 0.58 mmol) and DMSO were used to react in the same manner as in Step A of Example 72 to give the title compound (0.022 g, 19%).

[2745] <1>H-NMR (CDCl<3>) δ 8.22 (1H, m), 7.38 (1H, m), 7.19 (2H, m), 6.87 (1H, m), 4.22 (2H, t), 4.15 (2H, q), 3.03 (4H, m), 2.60 (2H, t), 2.11 (2H, m), 1.52 (6H, m), 1.27 (3H, t)[2745] <1>H-NMR (CDCl<3>) δ 8.22 (1H, m), 7.38 (1H, m), 7.19 (2H, m), 6.87 (1H, m), 4.22 (2H, t), 4.15 (2H, q), 3.03 (4H, m), 2.60 (2H, t), 2.11 (2H, m), 1.52 (6H, m), 1.27 (3H, t)

[2747] Faza B: 4-[2,6-difluoro-4-[2-(1-piperidil)-3-piridil]fenoksi]buterna kiselina[2747] Phase B: 4-[2,6-difluoro-4-[2-(1-piperidyl)-3-pyridyl]phenoxy]butyric acid

[2748] Etil 4-[2,6-difluoro-4-[2-(1-piperidil)-3-piridil]fenoksi]butanoat (0.021 g, 0.05 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.014 g, 74%).[2748] Ethyl 4-[2,6-difluoro-4-[2-(1-piperidyl)-3-pyridyl]phenoxy]butanoate (0.021 g, 0.05 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.014 g, 74%).

[2749] <1>H-NMR (CDCl<3>) δ 8.24 (1H, m), 7.40 (1H, m), 7.19 (2H, m), 6.89 (1H, m), 4.23 (2H, t), 3.05 (4H, m), 2.67 (2H, t), 2.13 (2H, m), 1.53 (6H, m)[2749] <1>H-NMR (CDCl<3>) δ 8.24 (1H, m), 7.40 (1H, m), 7.19 (2H, m), 6.89 (1H, m), 4.23 (2H, t), 3.05 (4H, m), 2.67 (2H, t), 2.13 (2H, m), 1.53 (6H, m)

[2751] Primer 114: (4S)-4-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]valerijanska kiselina [1075][2751] Example 114: (4S)-4-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]valeric acid [1075]

[2753] [2753]

[2756] Faza A: etil (4S)-4-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi] pentanoat[2756] Phase A: ethyl (4S)-4-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy] pentanoate

[2757] 2-ciklobutilsulfanil-3-jodo-piridin (0.077 g, 0.26 mmol) dobijen u primeru pripreme 44 i etil (4S)-4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]pentanoat (0.095 g, 0.24 mmol) dobijen u primeru pripreme 123 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.067 g, 60%).[2757] 2-cyclobutylsulfanyl-3-iodo-pyridine (0.077 g, 0.26 mmol) obtained in preparation example 44 and ethyl (4S)-4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pentanoate (0.095 g, 0.24 mmol) obtained in preparation example 44 123 were used to react in the same manner as in Step A of Example 28 to give the title compound (0.067 g, 60%).

[2758] 1H NMR (CDCl<3>) δ 8.41 (1H, m), 7.33 (1H, m), 7.00 (3H, m), 4.41 (2H, m), 4.16 (2H, q), 2.61 (2H, t), 2.60 (2H, m), 2.05 (6H, m), 1.33 (3H, d), 1.27 (3H, t)[2758] 1H NMR (CDCl<3>) δ 8.41 (1H, m), 7.33 (1H, m), 7.00 (3H, m), 4.41 (2H, m), 4.16 (2H, q), 2.61 (2H, t), 2.60 (2H, m), 2.05 (6H, m), 1.33 (3H, d), 1.27 (3H, t)

[2760] Faza B: (4S)-4-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]valerijanska kiselina[2760] Phase B: (4S)-4-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]valeric acid

[2761] Etil (4S)-4-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi] pentanoat (0.067 g, 0.16 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.033 g, 52%).[2761] Ethyl (4S)-4-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy] pentanoate (0.067 g, 0.16 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.033 g, 52%).

[2762] 1H NMR (CDCl<3>) δ 8.41 (1H, m), 7.33 (1H, m), 7.00 (3H, m), 4.41 (2H, m), 2.71 (2H, t), 2.52 (2H, m), 2.05 (6H, m), 1.35 (3H, d)[2762] 1H NMR (CDCl<3>) δ 8.41 (1H, m), 7.33 (1H, m), 7.00 (3H, m), 4.41 (2H, m), 2.71 (2H, t), 2.52 (2H, m), 2.05 (6H, m), 1.35 (3H, d)

[2763] Primer 115: (4R)-4-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]valerijanska kiselina [1080][2763] Example 115: (4R)-4-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]valeric acid [1080]

[2765] [2765]

[2768] Faza A: metil (4R)-4-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]pentanoat[2768] Phase A: methyl (4R)-4-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]pentanoate

[2769] 2-ciklobutilsulfanil-3-jodo-piridin (0.051 g, 0.18 mmol) dobijen u primeru pripreme 44 i metil (4R)-4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]pentanoat (0.062 g, 0.16 mmol) dobijen u primeru pripreme 117 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.04 g, 61%).[2769] 2-cyclobutylsulfanyl-3-iodo-pyridine (0.051 g, 0.18 mmol) obtained in preparation example 44 and methyl (4R)-4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pentanoate (0.062 g, 0.16 mmol) obtained in preparation example 44 117 were used to react in the same manner as in Step A of Example 28 to give the title compound (0.04 g, 61%).

[2770] 1H NMR (CDCl<3>) δ 8.41 (1H, m), 7.33 (1H, m), 7.01 (3H, m), 4.41 (2H, m), 3.69 (3H, s), 2.63 (2H, t), 2.51 (2H, m), 2.05 (6H, m), 1.33 (3H, d)[2770] 1H NMR (CDCl<3>) δ 8.41 (1H, m), 7.33 (1H, m), 7.01 (3H, m), 4.41 (2H, m), 3.69 (3H, s), 2.63 (2H, t), 2.51 (2H, m), 2.05 (6H, m), 1.33 (3H, d)

[2772] Faza B: (4R)-4-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi] valerijanska kiselina[2772] Phase B: (4R)-4-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy] valeric acid

[2773] Metil (4R)-4-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi] pentanoat (0.04 g, 0.1 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.039 g, 99%).[2773] Methyl (4R)-4-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy] pentanoate (0.04 g, 0.1 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.039 g, 99%).

[2774] 1H NMR (CDCl<3>) δ 8.41 (1H, m), 7.33 (1H, m), 7.00 (3H, m), 4.41 (2H, m), 2.71 (2H, t), 2.52 (2H, m), 2.05 (6H, m), 1.35 (3H, d)[2774] 1H NMR (CDCl<3>) δ 8.41 (1H, m), 7.33 (1H, m), 7.00 (3H, m), 4.41 (2H, m), 2.71 (2H, t), 2.52 (2H, m), 2.05 (6H, m), 1.35 (3H, d)

[2776] Primer 116: (4R)-4-[4-[3-(ciklobutoksi)fenil]-2,6-difluoro-fenoksi] valerijanska kiselina[2776] Example 116: (4R)-4-[4-[3-(cyclobutoxy)phenyl]-2,6-difluoro-phenoxy] valeric acid

[2777][2777]

[2779] [2779]

[2782] Faza A: metil (4R)-4-[4-[3-(ciklobutoksi)fenil]-2,6-difluoro-fenoksi] pentanoat[2782] Phase A: methyl (4R)-4-[4-[3-(cyclobutoxy)phenyl]-2,6-difluoro-phenoxy] pentanoate

[2783] 1-ciklobutoksi-3-jodo-benzen (0.049 g, 0.18 mmol) dobijen u primeru pripreme 60 i metil (4R)-4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]pentanoat (0.055 g, 0.15 mmol) dobijen u primeru pripreme 117 su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.039 g, 71%).[2783] 1-cyclobutoxy-3-iodo-benzene (0.049 g, 0.18 mmol) obtained in Preparation Example 60 and methyl (4R)-4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pentanoate (0.055 g, 0.15 mmol) obtained in Preparation Example 117 were used to react in the same manner as in Step A of Example 29 to give the title compound (0.039 g, 71%).

[2784] 1H NMR (CDCl<3>) δ 7.31 (1H, t), 7.09 (3H, m), 6.94 (1H, m), 6.80 (1H, m), 4.69 (1H, m), 4.34 (1H, m), 3.70 (3H, s), 2.62 (2H, t), 2.47 (2H, m), 2.20 (2H, m), 2.04 (2H, m), 1.88 (1H, m), 1.71 (1H, m), 1.31 (3H, d)[2784] 1H NMR (CDCl<3>) δ 7.31 (1H, t), 7.09 (3H, m), 6.94 (1H, m), 6.80 (1H, m), 4.69 (1H, m), 4.34 (1H, m), 3.70 (3H, s), 2.62 (2H, t), 2.47 (2H, m), 2.20 (2H, m), 2.04 (2H, m), 1.88 (1H, m), 1.71 (1H, m), 1.31 (3H, d)

[2785] Faza B: (4R)-4-[4-[3-(ciklobutoksi)fenil]-2,6-difluoro-fenoksi]valerijanska kiselina[2785] Phase B: (4R)-4-[4-[3-(cyclobutoxy)phenyl]-2,6-difluoro-phenoxy]valeric acid

[2786] Metil (4R)-4-[4-[3-(ciklobutoksi)fenil]-2,6-difluoro-fenoksi]pentanoat (0.039 g, 0.1 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.031 g, 82%).[2786] Methyl (4R)-4-[4-[3-(cyclobutoxy)phenyl]-2,6-difluoro-phenoxy]pentanoate (0.039 g, 0.1 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.031 g, 82%).

[2787] 1H NMR (CDCl<3>) δ 7.31 (1H, t), 7.12 (3H, m), 6.95 (1H, m), 6.80 (1H, m), 4.69 (1H, m), 4.36 (1H, m), 2.70 (2H, t), 2.46 (2H, m), 2.20 (2H, m), 2.05 (2H, m), 1.88 (1H, m), 1.71 (1H, m), 1.30 (3H, d)[2787] 1H NMR (CDCl<3>) δ 7.31 (1H, t), 7.12 (3H, m), 6.95 (1H, m), 6.80 (1H, m), 4.69 (1H, m), 4.36 (1H, m), 2.70 (2H, t), 2.46 (2H, m), 2.20 (2H, m), 2.05 (2H, m), 1.88 (1H, m), 1.71 (1H, m), 1.30 (3H, d)

[2789] Primer 117: (4R)-4-[4-(2-ciklopentilsulfanil-3-piridil)-2,6-difluoro-fenoksi] valerijanska kiselina [1090][2789] Example 117: (4R)-4-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy] valeric acid [1090]

[2791] [2791]

[2794] Faza A; metil (4R)-4-[4-(2-ciklopentilsulfanil-3-piridil)-2,6-difluoro-fenoksi]pentanoat[2794] Phase A; methyl (4R)-4-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]pentanoate

[2795] 2-ciklopentilsulfanil-3-jodo-piridin (0.054 g, 0.18 mmol) dobijen u primeru pripreme 39 i metil (4R)-4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]pentanoat (0.055 g, 0.15 mmol) dobijen u primeru pripreme 117 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.045 g, 66%).[2795] 2-cyclopentylsulfanyl-3-iodo-pyridine (0.054 g, 0.18 mmol) obtained in preparation example 39 and methyl (4R)-4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pentanoate (0.055 g, 0.15 mmol) obtained in preparation example 39 117 were used to react in the same manner as in Step A of Example 28 to give the title compound (0.045 g, 66%).

[2796] 1H NMR (CDCl<3>) δ 8.42 (1H, m), 7.32 (1H, m), 7.00 (3H, m), 4.37 (1H, m), 4.08 (1H, m), 3.70 (3H, s), 2.63 (2H, t), 2.20 (2H, m), 2.04 (2H, m), 1.72 (2H, m), 1.64 (2H, m), 1.57 (2H, m), 1.33 (3H, d)[2796] 1H NMR (CDCl<3>) δ 8.42 (1H, m), 7.32 (1H, m), 7.00 (3H, m), 4.37 (1H, m), 4.08 (1H, m), 3.70 (3H, s), 2.63 (2H, t), 2.20 (2H, m), 2.04 (2H, m), 1.72 (2H, m), 1.64 (2H, m), 1.57 (2H, m), 1.33 (3H, d)

[2798] Faza B: (4R)-4-[4-(2-ciklopentilsulfanil-3-piridil)-2,6-difluoro-fenoksi] valerijanska kiselina[2798] Phase B: (4R)-4-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy] valeric acid

[2799] Metil (4R)-4-[4-(2-ciklopentilsulfanil-3-piridil)-2,6-difluoro-fenoksi] pentanoat (0.045 g, 0.1 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.041 g, 95%).[2799] Methyl (4R)-4-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy] pentanoate (0.045 g, 0.1 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.041 g, 95%).

[2800] 1H NMR (CDCl<3>) δ 8.43 (1H, m), 7.32 (1H, m), 7.00 (3H, m), 4.39 (1H, m), 4.09 (1H, m), 2.70 (2H, t), 2.20 (2H, m), 2.04 (2H, m), 1.71 (2H, m), 1.62 (4H, m), 1.34 (3H, d)[2800] 1H NMR (CDCl<3>) δ 8.43 (1H, m), 7.32 (1H, m), 7.00 (3H, m), 4.39 (1H, m), 4.09 (1H, m), 2.70 (2H, t), 2.20 (2H, m), 2.04 (2H, m), 1.71 (2H, m), 1.62 (4H, m), 1.34 (3H, d)

[2802] Primer 118: (4R)-4-[2,6-difluoro-4-(3-fenoksifenil)fenoksi]valerijanska kiselina[2802] Example 118: (4R)-4-[2,6-difluoro-4-(3-phenoxyphenyl)phenoxy]valeric acid

[2803][2803]

[2805] [2805]

[2806] Faza A: metil (4R)-4-[2,6-difluoro-4-(3-fenoksil)fenil)fenoksi]pentanoat[2806] Phase A: methyl (4R)-4-[2,6-difluoro-4-(3-phenoxyl)phenyl)phenoxy]pentanoate

[2807] Metil (4R)-4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il) fenoksi]pentanoat (0.055 g, 0.15 mmol) dobijen u primeru pripreme 117 i 1-bromo-3-fenoksi-benzen (0.044 g, 0.18 mmol) su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.044 g, 72%).[2807] Methyl (4R)-4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pentanoate (0.055 g, 0.15 mmol) obtained in Preparation Example 117 and 1-bromo-3-phenoxy-benzene (0.044 g, 0.18 mmol) were used to react the same as in Step A of Example 29 to give the title compound (0.044 g, 72%).

[2808] 1H NMR (CDCl<3>) δ 7.37 (3H, m), 7.23 (1H, m), 7.14 (2H, m), 7.08 (2H, m), 7.04 (2H, m), 6.99 (1H, m), 4.34 (1H, m), 3.69 (3H, s), 2.62 (2H, t), 2.02 (2H, m), 1.30 (3H, d)[2808] 1H NMR (CDCl<3>) δ 7.37 (3H, m), 7.23 (1H, m), 7.14 (2H, m), 7.08 (2H, m), 7.04 (2H, m), 6.99 (1H, m), 4.34 (1H, m), 3.69 (3H, s), 2.62 (2H, t), 2.02 (2H, m), 1.30 (3H, d)

[2810] Faza B: (4R)-4-[2,6-difluoro-4-(3-fenoksifenil)fenoksi]valerijanska kiselina[2810] Phase B: (4R)-4-[2,6-difluoro-4-(3-phenoxyphenyl)phenoxy]valeric acid

[2811] Metil (4R)-4-[2,6-difluoro-4-(3-fenoksifenil)fenoksi]pentanoat (0.044 g, 0.1 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.041 g, 96%).[2811] Methyl (4R)-4-[2,6-difluoro-4-(3-phenoxyphenyl)phenoxy]pentanoate (0.044 g, 0.1 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.041 g, 96%).

[2812] 1H NMR (CDCl<3>) δ 7.36 (3H, m), 7.23 (1H, m), 7.14 (2H, m), 7.09 (2H, m), 7.04 (2H, m), 6.99 (1H, m), 4.35 (1H, m), 2.68 (2H, t), 2.03 (2H, m), 1.30 (3H, d)[2812] 1H NMR (CDCl<3>) δ 7.36 (3H, m), 7.23 (1H, m), 7.14 (2H, m), 7.09 (2H, m), 7.04 (2H, m), 6.99 (1H, m), 4.35 (1H, m), 2.68 (2H, t), 2.03 (2H, m), 1.30 (3H, d)

[2814] Primer 119: 4-(3'-ciklobutoksi-bifenil-4-ilsulfanil)-buterna kiselina[2814] Example 119: 4-(3'-cyclobutoxy-biphenyl-4-ylsulfanyl)-butyric acid

[2815][2815]

[2817] [2817]

[2820] Faza A: etil estar 4-(3'-ciklobutoksi-bifenil-4-ilsulfanil)-buterne kiseline[2820] Phase A: 4-(3'-cyclobutoxy-biphenyl-4-ylsulfanyl)-butyric acid ethyl ester

[2821] Etil estar 4-(3'-hidroksi-bifenil-4-ilsulfanil)-buterne kiseline (0.1 g, 0.32 mmol) dobijen u primeru pripreme 149, bromo-ciklobutan (0.044 mL) i Cs<2>CO<3>(0.31 g, 0.95 mmol) su korišćeni da bi reagovali na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.075 g, 64%).[2821] 4-(3'-Hydroxy-biphenyl-4-ylsulfanyl)-butyric acid ethyl ester (0.1 g, 0.32 mmol) obtained in Preparative Example 149, bromo-cyclobutane (0.044 mL) and Cs<2>CO<3> (0.31 g, 0.95 mmol) were used to react in the same manner as in Step B of Preparative Example 44 to give title compound (0.075 g, 64%).

[2822] <1>H-NMR (CDCl<3>) δ 7.48 (2H, d), 7.38 (2H, d), 7.30 (1H, t), 7.12 (1H, m), 7.00 (1H, s), 6.78 (1H, m), 4.69 (1H, m), 4.12 (2H, q), 3.00 (2H, t), 2.47 (4H, m), 2.20 (2H, m), 1.98 (2H, m), 1.86 (1H, m), 1.70 (1H, m), 1.24 (3H, t).[2822] <1>H-NMR (CDCl<3>) δ 7.48 (2H, d), 7.38 (2H, d), 7.30 (1H, t), 7.12 (1H, m), 7.00 (1H, s), 6.78 (1H, m), 4.69 (1H, m), 4.12 (2H, q), 3.00 (2H, t), 2.47 (4H, m), 2.20 (2H, m), 1.98 (2H, m), 1.86 (1H, m), 1.70 (1H, m), 1.24 (3H, t).

[2824] Faza B: 4-(3'-ciklobutoksi-bifenil-4-ilsulfanil)-buterna kiselina[2824] Phase B: 4-(3'-cyclobutoxy-biphenyl-4-ylsulfanyl)-butyric acid

[2825] Etil estar 4-(3'-ciklobutoksi-bifenil-4-ilsulfanil)-buterne kiseline (0.075 g, 0.20 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.02 g, 28%).[2825] 4-(3'-Cyclobutoxy-biphenyl-4-ylsulfanyl)-butyric acid ethyl ester (0.075 g, 0.20 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.02 g, 28%).

[2826] <1>H-NMR (CDCl<3>) δ 7.48 (2H, d), 7.38 (2H, d), 7.30 (1H, t), 7.12 (1H, m), 7.00 (1H, s), 6.78 (1H, m), 4.68 (1H, m), 3.01 (2H, t), 2.54 (2H, t), 2.46 (2H, m), 2.20 (2H, m), 2.00 (2H, m), 1.85 (1H, m), 1.70 (1H, m).[2826] <1>H-NMR (CDCl<3>) δ 7.48 (2H, d), 7.38 (2H, d), 7.30 (1H, t), 7.12 (1H, m), 7.00 (1H, s), 6.78 (1H, m), 4.68 (1H, m), 3.01 (2H, t), 2.54 (2H, t), 2.46 (2H, m), 2.20 (2H, m), 2.00 (2H, m), 1.85 (1H, m), 1.70 (1H, m).

[2828] Primer 120: 4-(3'-izopropoksi-bifenil-4-ilsulfanil)-buterna kiselina[2828] Example 120: 4-(3'-isopropoxy-biphenyl-4-ylsulfanyl)-butyric acid

[2829][2829]

[2831] [2831]

[2834] Faza A: etil estar 4-(3'-izopropoksi-bifenil-4-ilsulfanil)-buterne kiseline[2834] Phase A: 4-(3'-isopropoxy-biphenyl-4-ylsulfanyl)-butyric acid ethyl ester

[2835] Etil estar 4-(3'-hidroksi-bifenil-4-ilsulfanil)-buterne kiseline (0.11 g, 0.35 mmol) dobijen u primeru pripreme 149, 2-bromo-propan (0.049 mL) i Cs<2>CO<3>(0.34 g, 1.04 mmol) su korišćeni da bi reagovali na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.12 g, 96%).[2835] 4-(3'-Hydroxy-biphenyl-4-ylsulfanyl)-butyric acid ethyl ester (0.11 g, 0.35 mmol) obtained in Preparative Example 149, 2-bromo-propane (0.049 mL) and Cs<2>CO<3> (0.34 g, 1.04 mmol) were used to react in the same manner as in Step B of Preparative Example 44 to give obtained the title compound (0.12 g, 96%).

[2836] <1>H-NMR (CDCl<3>) δ 7.50 (2H, d), 7.39 (2H, d), 7.31 (1H, t), 7.12 (1H, m), 7.07 (1H, s), 6.86 (1H, m), 4.60 (1H, m), 4.13 (2H, q), 3.00 (2H, t), 2.47 (2H, t), 1.98 (2H, m), 1.36 (6H, d), 1.24 (3H, t).[2836] <1>H-NMR (CDCl<3>) δ 7.50 (2H, d), 7.39 (2H, d), 7.31 (1H, t), 7.12 (1H, m), 7.07 (1H, s), 6.86 (1H, m), 4.60 (1H, m), 4.13 (2H, q), 3.00 (2H, t), 2.47 (2H, t), 1.98 (2H, m), 1.36 (6H, d), 1.24 (3H, t).

[2838] Faza B: 4-(3'-izopropoksi-bifenil-4-ilsulfanil)-buterna kiselina[2838] Phase B: 4-(3'-isopropoxy-biphenyl-4-ylsulfanyl)-butyric acid

[2839] Etil estar 4-(3'-izopropoksi-bifenil-4-ilsulfanil)-buterne kiseline (0.12 g, 0.33 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.10 g, 95%).[2839] 4-(3'-Isopropoxy-biphenyl-4-ylsulfanyl)-butyric acid ethyl ester (0.12 g, 0.33 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.10 g, 95%).

[2840] <1>H-NMR (CDCl<3>) δ 7.50 (2H, d), 7.39 (2H, d), 7.31 (1H, t), 7.12 (1H, m), 7.07 (1H, s), 6.86 (1H, m), 4.60 (1H, m), 3.01 (2H, t), 2.54 (2H, t), 2.00 (2H, m), 1.34 (6H, d).[2840] <1>H-NMR (CDCl<3>) δ 7.50 (2H, d), 7.39 (2H, d), 7.31 (1H, t), 7.12 (1H, m), 7.07 (1H, s), 6.86 (1H, m), 4.60 (1H, m), 3.01 (2H, t), 2.54 (2H, t), 2.00 (2H, m), 1.34 (6H, d).

[2842] Primer 121: [1-(3,5-difluoro-3'-izopropoksi-bifenil-4-ilsulfanilmetil)-ciklopropil]-sirćetna kiselina [1110][2842] Example 121: [1-(3,5-difluoro-3'-isopropoxy-biphenyl-4-ylsulfanylmethyl)-cyclopropyl]-acetic acid [1110]

[2844] [2844]

[2846] Faza A: metil estar [1-(3,5-difluoro-3'-izopropoksi-bifenil-4-ilsulfanilmetil)-ciklopropil]-sirćetne kiseline [1111] Metil estar [1-(3,5-difluoro-3'-hidroksi-bifenil-4-ilsulfanilmetil)-ciklopropil]-sirćetne kiseline (0.02 g, 0.05 mmol) dobijen u primeru pripreme 152, 2-bromo-propan (0.008 mL) i Cs<2>CO<3>(0.05 g, 0.16 mmol) su korišćeni da bi reagovali na isti način kao u fazi B primera pripreme 44 da bi se dobilo naslovno jedinjenje (0.006 g, 27%).[2846] Phase A: [1-(3,5-difluoro-3'-isopropoxy-biphenyl-4-ylsulfanylmethyl)-cyclopropyl]-acetic acid methyl ester [1-(3,5-difluoro-3'-hydroxy-biphenyl-4-ylsulfanylmethyl)-cyclopropyl]-acetic acid methyl ester (0.02 g, 0.05 mmol) obtained in preparation example 152, 2-Bromo-propane (0.008 mL) and Cs<2>CO<3> (0.05 g, 0.16 mmol) were used to react in the same manner as in Step B of Preparation Example 44 to give the title compound (0.006 g, 27%).

[2847] <1>H-NMR (CDCl<3>) δ 7.34 (1H, t), 7.13-7.08 (3H, m), 7.04 (1H, s), 6.91 (1H, m), 4.61 (1H, m), 3.64 (3H, s), 3.01 (2H, s), 2.56 (2H, s), 1.35 (6H, d), 0.45-0.38 (4H, m).[2847] <1>H-NMR (CDCl<3>) δ 7.34 (1H, t), 7.13-7.08 (3H, m), 7.04 (1H, s), 6.91 (1H, m), 4.61 (1H, m), 3.64 (3H, s), 3.01 (2H, s), 2.56 (2H, s), 1.35 (6H, d), 0.45-0.38 (4H, m).

[2848] Faza B: [1-(3,5-difluoro-3'-izopropoksi-bifenil-4-ilsulfanilmetil)-ciklopropil]-sirćetna kiselina [1113] Metil estar [1-(3,5-difluoro-3'-izopropoksi-bifenil-4-ilsulfanilmetil)-ciklopropil]-sirćetne kiseline (0.006 g, 0.015 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.004 g, 69%).[2848] Phase B: [1-(3,5-difluoro-3'-isopropoxy-biphenyl-4-ylsulfanylmethyl)-cyclopropyl]-acetic acid [1113] [1-(3,5-difluoro-3'-isopropoxy-biphenyl-4-ylsulfanylmethyl)-cyclopropyl]-acetic acid methyl ester (0.006 g, 0.015 mmol) obtained in phase A was used to would react in the same manner as in step B of Example 1 to give the title compound (0.004 g, 69%).

[2849] <1>H-NMR (CDCl<3>) δ 7.33 (1H, t), 7.13-7.05 (4H, m), 6.90 (1H, m), 4.60 (1H, m), 3.01 (2H, s), 2.62 (2H, s), 1.36 (6H, d), 0.46-0.35 (4H, m).[2849] <1>H-NMR (CDCl<3>) δ 7.33 (1H, t), 7.13-7.05 (4H, m), 6.90 (1H, m), 4.60 (1H, m), 3.01 (2H, s), 2.62 (2H, s), 1.36 (6H, d), 0.46-0.35 (4H, m).

[2851] Primer 122: 4-(3'-ciklopentiloksi-3,5-difluoro-bifenil-4-ilsulfanil)-buterna kiselina[2851] Example 122: 4-(3'-cyclopentyloxy-3,5-difluoro-biphenyl-4-ylsulfanyl)-butyric acid

[2852][2852]

[2854] [2854]

[2857] Faza A: dimetil estar 2-[2-(3'-ciklopentiloksi-3,5-difluoro-bifenil-ilsulfanil)-etil]-malonske kiseline [1116] NaH (60% u mineralnom ulju, 0.005 g, 0.12 mmol) je rastvoren u 1mL DMF-a. Dodat je dimetilmalonat (0.013 mL, 0,12 mmol) i proizvod je mešan na sobnoj temperaturi 15 minuta. Dodat je 4-(2-hloro-etilsulfanil)-3'-ciklopentiloksi-3,5-difluoro-bifenil (0.03 g, 0.08 mmol) dobijen u primeru pripreme 158, i proizvod je mešan 18 sati na 65°C. Reakcionom rastvoru je dodata voda i ekstrahovan je sa EtOAc. Organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.01 g, 25 %).[2857] Phase A: 2-[2-(3'-cyclopentyloxy-3,5-difluoro-biphenyl-ylsulfanyl)-ethyl]-malonic acid dimethyl ester [1116] NaH (60% in mineral oil, 0.005 g, 0.12 mmol) was dissolved in 1 mL of DMF. Dimethylmalonate (0.013 mL, 0.12 mmol) was added and the product was stirred at room temperature for 15 min. 4-(2-Chloro-ethylsulfanyl)-3'-cyclopentyloxy-3,5-difluoro-biphenyl (0.03 g, 0.08 mmol) obtained in Preparative Example 158 was added, and the product was stirred for 18 hours at 65°C. Water was added to the reaction solution and extracted with EtOAc. The organic layer was dried with MgSO4 and purified by column chromatography to give the title compound (0.01 g, 25 %).

[2859] Faza B: 4-(3'-ciklopentiloksi-3,5-difluoro-bifenil-ilsulfanil)-buterna kiselina[2859] Phase B: 4-(3'-cyclopentyloxy-3,5-difluoro-biphenyl-ylsulfanyl)-butyric acid

[2860] Dimetil estar 2-[2-(3'-ciklopentiloksi-3,5-difluoro-bifenil-ilsulfanil)-etil]-malonske kiseline (0.01 g, 0.02 mmol) dobijen u fazi A je rastvoren u po 0.3 mL EtOH-a i THF-a. Dodato je 0.2 mL od 4N KOH, i proizvod je mešan 1 sat na 60°C. Reakcioni rastvor je koncentrovan pod smanjenim pritiskom, i dodata je voda. pH je podešena na 3 upotrebom 2N HCl, i proizvod je zatim ekstrahovan sa EtOAc. Odvojeni organski sloj je osušen sa MgSO<4>i koncentrovan pod smanjenim pritiskom. Koncentrovani organski sloj je rastvoren u 1 mL piridina, i proizvod je mešan 18 sati na 80°C. Reakcioni rastvor je koncentrovan pod smanjenim pritiskom, a zatim je dodata voda. pH je podešena na 3 upotrebom 2N HCl, i proizvod je zatim ekstrahovan sa EtOAc. Odvojeni organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.002 g, 20 %).[2860] 2-[2-(3'-cyclopentyloxy-3,5-difluoro-biphenyl-ylsulfanyl)-ethyl]-malonic acid dimethyl ester (0.01 g, 0.02 mmol) obtained in step A was dissolved in 0.3 mL each of EtOH and THF. 0.2 mL of 4N KOH was added, and the product was stirred for 1 hour at 60°C. The reaction solution was concentrated under reduced pressure, and water was added. The pH was adjusted to 3 using 2N HCl, and the product was then extracted with EtOAc. The separated organic layer was dried with MgSO4 and concentrated under reduced pressure. The concentrated organic layer was dissolved in 1 mL of pyridine, and the product was stirred for 18 hours at 80°C. The reaction solution was concentrated under reduced pressure, and then water was added. The pH was adjusted to 3 using 2N HCl, and the product was then extracted with EtOAc. The separated organic layer was dried with MgSO4 and purified by column chromatography to give the title compound (0.002 g, 20 %).

[2861] <1>H-NMR (CDCl<3>) δ 7.32 (1H, t), 7.13 (2H, m), 7.08 (1H, m), 7.02 (1H, s), 6.90 (1H, m), 4.81 (1H, m), 2.94 (2H, t), 2.55 (2H, t), 1.92-1.81 (8H, m), 1.64 (2H, m).[2861] <1>H-NMR (CDCl<3>) δ 7.32 (1H, t), 7.13 (2H, m), 7.08 (1H, m), 7.02 (1H, s), 6.90 (1H, m), 4.81 (1H, m), 2.94 (2H, t), 2.55 (2H, t), 1.92-1.81 (8H, m), 1.64 (2H, m).

[2862] Primer 123: 4-[4-(2-ciklopentiloksi-piridin-3-il)-fenilsulfanil]-buterna kiselina[2862] Example 123: 4-[4-(2-cyclopentyloxy-pyridin-3-yl)-phenylsulfanyl]-butyric acid

[2863][2863]

[2865] [2865]

[2868] Etil estar 4-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.056 g, 0.16 mmol) dobijen u primeru pripreme 159 i 2-ciklopentoksi-3-jodo-piridin (0.046 g, 0.16 mmol) dobijen u primeru pripreme 38 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.025 g, 44%).[2868] 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.056 g, 0.16 mmol) obtained in Preparation Example 159 and 2-cyclopentoxy-3-iodo-pyridine (0.046 g, 0.16 mmol) obtained in Preparation Example 38 were used to reacted in the same manner as in steps A and B of Example 1 to give the title compound (0.025 g, 44%).

[2869] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.56 (1H, m), 7.49 (2H, d), 7.36 (2H, d), 6.90 (1H, m), 5.50 (1H, m), 3.02 (2H, t), 2.56 (2H, t), 2.03-1.92 (4H, m), 1.84-1.60 (6H, m).[2869] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.56 (1H, m), 7.49 (2H, d), 7.36 (2H, d), 6.90 (1H, m), 5.50 (1H, m), 3.02 (2H, t), 2.56 (2H, t), 2.03-1.92 (4H, m), 1.84-1.60 (6H, m).

[2871] Primer 124: 4-[4-(2-ciklopropilmetoksi-piridin-3-il)-fenilsulfanil]-buterna kiselina[2871] Example 124: 4-[4-(2-cyclopropylmethoxy-pyridin-3-yl)-phenylsulfanyl]-butyric acid

[2872][2872]

[2874] [2874]

[2877] Etil estar 4-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.08 g, 0.29 mmol) dobijen u primeru pripreme 159 i 2-ciklopropilmetoksi-3-jodo-piridin (0.10 g, 0.29 mmol) dobijen u primeru pripreme 40 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.02 g, 25%).[2877] 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.08 g, 0.29 mmol) obtained in Preparation Example 159 and 2-cyclopropylmethoxy-3-iodo-pyridine (0.10 g, 0.29 mmol) obtained in Preparation Example 40 were used to reacted in the same manner as in steps A and B of Example 1 to give the title compound (0.02 g, 25%).

[2878] <1>H-NMR (CDCl<3>) δ 8.10 (1H, m), 7.59 (1H, m), 7.55 (2H, d), 7.38 (2H, d), 6.95 (1H, m), 4.20 (2H, d), 3.04-3.01 (2H, t), 2.57-2.54 (2H, t), 2.02-1.99 (2H, m), 1.27 (1H, m), 0.55 (2H, m), 0.33 (2H, m).[2878] <1>H-NMR (CDCl<3>) δ 8.10 (1H, m), 7.59 (1H, m), 7.55 (2H, d), 7.38 (2H, d), 6.95 (1H, m), 4.20 (2H, d), 3.04-3.01 (2H, t), 2.57-2.54 (2H, t), 2.02-1.99 (2H, m), 1.27 (1H, m), 0.55 (2H, m), 0.33 (2H, m).

[2880] Primer 125: 4-(3'-fenoksi-bifenil-4-ilsulfanil)-buterna kiselina[2880] Example 125: 4-(3'-phenoxy-biphenyl-4-ylsulfanyl)-butyric acid

[2881][2881]

[2883] [2883]

[2886] Etil estar 4-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.03 g, 0.11 mmol) dobijen u primeru pripreme 159 i 1-bromo-3-fenoksi-benzen (0.03 g, 0.12 mmol) su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.005 g, 16%).[2886] 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.03 g, 0.11 mmol) obtained in Preparative Example 159 and 1-bromo-3-phenoxy-benzene (0.03 g, 0.12 mmol) were used to react in the same manner as in steps A and B. of Example 1 to give the title compound (0.005 g, 16%).

[2887] <1>H-NMR (CDCl<3>) δ 7.48 (2H, d), 7.38-7.26 (6H, m), 7.25 (1H, s), 7.1 (1H, t), 7.05 (2H, d), 6.97 (1H, m), 3.00 (2H, t), 2.54 (2H, t), 1.98 (2H, m).[2887] <1>H-NMR (CDCl<3>) δ 7.48 (2H, d), 7.38-7.26 (6H, m), 7.25 (1H, s), 7.1 (1H, t), 7.05 (2H, d), 6.97 (1H, m), 3.00 (2H, t), 2.54 (2H, t), 1.98 (2H, m).

[2889] Primer 126: 4-(3'-ciklopentiloksi-bifenil-4-ilsulfanil)-buterna kiselina[2889] Example 126: 4-(3'-cyclopentyloxy-biphenyl-4-ylsulfanyl)-butyric acid

[2890][2890]

[2892] [2892]

[2895] Etil estar 4-(3'-hidroksi-bifenil-4-ilsulfanil)-buterne kiseline (0.056 g, 0.17 mmol) dobijen u primeru pripreme 149, bromo-ciklopentan (0.030 mL) i Cs<2>CO<3>(0.17 g, 0.53 mmol) su korišćeni da bi reagovali na isti način kao u fazama A i B primera 119 da bi se dobilo naslovno jedinjenje (0.052 g, 82%).[2895] 4-(3'-Hydroxy-biphenyl-4-ylsulfanyl)-butyric acid ethyl ester (0.056 g, 0.17 mmol) obtained in Preparation Example 149, bromo-cyclopentane (0.030 mL) and Cs<2>CO<3> (0.17 g, 0.53 mmol) were used to react in the same manner as in steps A and B of Example 119. to give the title compound (0.052 g, 82%).

[2896] <1>H-NMR (CDCl<3>) δ 7.49 (2H, d), 7.38 (2H, d), 7.30 (1H, t), 7.12 (1H, m), 7.06 (1H, s), 6.85 (1H, m), 4.81 (1H, m), 3.01 (2H, t), 2.54 (2H, t), 2.00-1.81 (8H, m), 1.62 (2H, m).[2896] <1>H-NMR (CDCl<3>) δ 7.49 (2H, d), 7.38 (2H, d), 7.30 (1H, t), 7.12 (1H, m), 7.06 (1H, s), 6.85 (1H, m), 4.81 (1H, m), 3.01 (2H, t), 2.54 (2H, t), 2.00-1.81 (8H, m), 1.62 (2H, m).

[2898] Primer 127: 4-(3'-propoksi-bifenil-4-ilsulfanil)-buterna kiselina[2898] Example 127: 4-(3'-propoxy-biphenyl-4-ylsulfanyl)-butyric acid

[2899][2899]

[2901] [2901]

[2904] Etil estar 4-(3'-hidroksi-bifenil-4-ilsulfanil)-buterne kiseline (0.053 g, 0.17 mmol) dobijen u primeru pripreme 149, 2-bromo-propan (0.023 mL) i Cs<2>CO<3>(0.16 g, 0.50 mmol) su korišćeni da bi reagovali na isti način kao u fazama A i B primera 119 da bi se dobilo naslovno jedinjenje (0.045 g, 81%).[2904] 4-(3'-Hydroxy-biphenyl-4-ylsulfanyl)-butyric acid ethyl ester (0.053 g, 0.17 mmol) obtained in Preparation Example 149, 2-bromo-propane (0.023 mL) and Cs<2>CO<3> (0.16 g, 0.50 mmol) were used to react in the same manner as in steps A and B of Example 119. to give the title compound (0.045 g, 81%).

[2905] <1>H-NMR (CDCl<3>) δ 7.50 (2H, d), 7.38 (2H, d), 7.32 (1H, t), 7.12 (1H, m), 7.09 (1H, s), 6.87 (1H, m), 3.97 (2H, t), 3.01 (2H, t), 2.55 (2H, t), 2.00 (2H, m), 1.82 (2H, m), 1.05 (3H, t).[2905] <1>H-NMR (CDCl<3>) δ 7.50 (2H, d), 7.38 (2H, d), 7.32 (1H, t), 7.12 (1H, m), 7.09 (1H, s), 6.87 (1H, m), 3.97 (2H, t), 3.01 (2H, t), 2.55 (2H, t), 2.00 (2H, m), 1.82 (2H, m), 1.05 (3H, t).

[2907] Primer 128: 4-[4-(6-ciklobutoksi-piridin-2-il)-fenilsulfanil]-buterna kiselina[2907] Example 128: 4-[4-(6-cyclobutoxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid

[2908][2908]

[2910] [2910]

[2913] Etil estar 4-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 159 i 2-hloro-6-(ciklobutoksi)-piridin (0.033 g, 0.16 mmol) dobijen u primeru pripreme 24 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.005 g, 10%).[2913] 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 159 and 2-chloro-6-(cyclobutoxy)-pyridine (0.033 g, 0.16 mmol) obtained in Preparation Example 24 were used to reacted in the same manner as in steps A and B of Example 1 to give the title compound (0.005 g, 10%).

[2914] <1>H-NMR (CDCl<3>) δ 7.93 (2H, d), 7.59 (1H, t), 7.38 (2H, d), 7.28 (1H, d), 6.61 (1H, d), 5.26 (1H, m), 3.02 (2H, t), 2.56-2.53 (4H, m), 2.19 (2H, m), 2.01 (2H, m), 1.85 (1H, q), 1.73 (1H, m).[2914] <1>H-NMR (CDCl<3>) δ 7.93 (2H, d), 7.59 (1H, t), 7.38 (2H, d), 7.28 (1H, d), 6.61 (1H, d), 5.26 (1H, m), 3.02 (2H, t), 2.56-2.53 (4H, m), 2.19 (2H, m), 2.01 (2H, m), 1.85 (1H, q), 1.73 (1H, m).

[2916] Primer 129: 4-[4-(6-ciklopentiloksi-piridin-2-il)-fenilsulfanil]-buterna kiselina[2916] Example 129: 4-[4-(6-cyclopentyloxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid

[2917][2917]

[2919] [2919]

[2922] Etil estar 4-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 159 i 2-hloro-6-(ciklopentoksi)piridin (0.036 g, 0.16 mmol) dobijen u primeru pripreme 8 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.004 g, 8%).[2922] 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 159 and 2-chloro-6-(cyclopentoxy)pyridine (0.036 g, 0.16 mmol) obtained in Preparation Example 8 were used to reacted in the same manner as in steps A and B of Example 1 to give the title compound (0.004 g, 8%).

[2923] <1>H-NMR (CDCl<3>) δ 7.95 (2H, d), 7.57 (1H, t), 7.38 (2H, d), 7.26 (1H, d), 6.60 (1H, d), 5.50 (1H, m), 3.02 (2H, t), 2.54 (2H, t), 2.10-1.97 (4H, m), 1.82 (4H, m), 1.63 (2H, m).[2923] <1>H-NMR (CDCl<3>) δ 7.95 (2H, d), 7.57 (1H, t), 7.38 (2H, d), 7.26 (1H, d), 6.60 (1H, d), 5.50 (1H, m), 3.02 (2H, t), 2.54 (2H, t), 2.10-1.97 (4H, m), 1.82 (4H, m), 1.63 (2H, m).

[2925] Primer 130: 4-[4-(6-izopropoksi-piridin-2-il)-fenilsulfanil]-buterna kiselina[2925] Example 130: 4-[4-(6-isopropoxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid

[2926][2926]

[2928] [2928]

[2931] Etil estar 4-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.031 g, 0.09 mmol) dobijen u primeru pripreme 159 i 2-bromo-6-izopropoksi-piridin (0.021 g, 0.10 mmol) dobijen u primeru pripreme 228 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.011 g, 37%).[2931] 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.031 g, 0.09 mmol) obtained in Preparation Example 159 and 2-bromo-6-isopropoxy-pyridine (0.021 g, 0.10 mmol) obtained in Preparation Example 228 were used to reacted in the same manner as in steps A and B of Example 1 to give the title compound (0.011 g, 37%).

[2932] <1>H-NMR (CDCl<3>) δ 7.94 (2H, d), 7.59 (1H, t), 7.38 (2H, d), 7.26 (1H, d), 6.60 (1H, d), 5.46 (1H, m), 3.02 (2H, t), 2.54 (2H, t), 2.00 (2H, m), 1.39 (6H, d).[2932] <1>H-NMR (CDCl<3>) δ 7.94 (2H, d), 7.59 (1H, t), 7.38 (2H, d), 7.26 (1H, d), 6.60 (1H, d), 5.46 (1H, m), 3.02 (2H, t), 2.54 (2H, t), 2.00 (2H, m), 1.39 (6H, d).

[2933] Primer 131: 4-[4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-buterna kiselina[2933] Example 131: 4-[4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-butyric acid

[2934][2934]

[2936] [2936]

[2939] Etil estar 4-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.11 g, 0.32 mmol) dobijen u primeru pripreme 159 i 3-jodo-2-izopropoksi-piridin (0.12 g, 0.35 mmol) dobijen u primeru pripreme 37 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.05 g, 34%).[2939] 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.11 g, 0.32 mmol) obtained in Preparation Example 159 and 3-iodo-2-isopropoxy-pyridine (0.12 g, 0.35 mmol) obtained in Preparation Example 37 were used to reacted in the same manner as in steps A and B of Example 1 to give the title compound (0.05 g, 34%).

[2940] <1>H-NMR (CDCl<3>) δ 8.11 (1H, m), 7.57 (1H, m), 7.50 (2H, d), 7.35 (2H, d), 6.90 (1H, m), 5.38 (1H, m), 3.02 (2H, t), 2.56 (2H, t), 2.02 (2H, m), 1.33 (6H, d).[2940] <1>H-NMR (CDCl<3>) δ 8.11 (1H, m), 7.57 (1H, m), 7.50 (2H, d), 7.35 (2H, d), 6.90 (1H, m), 5.38 (1H, m), 3.02 (2H, t), 2.56 (2H, t), 2.02 (2H, m), 1.33 (6H, d).

[2942] Primer 132: 4-[4-(6-propoksi-piridin-2-il)-fenilsulfanil]-buterna kiselina[2942] Example 132: 4-[4-(6-propoxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid

[2943][2943]

[2945] [2945]

[2948] Etil estar 4-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.06 g, 0.17 mmol) dobijen u primeru pripreme 159 i 2-bromo-6-propoksi-piridin (0.041 g, 0.19 mmol) dobijen u primeru pripreme 227 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.03 g, 52%).[2948] 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.06 g, 0.17 mmol) obtained in Preparation Example 159 and 2-bromo-6-propoxy-pyridine (0.041 g, 0.19 mmol) obtained in Preparation Example 227 were used to reacted in the same manner as in steps A and B of Example 1 to give the title compound (0.03 g, 52%).

[2949] <1>H-NMR (CDCl<3>) δ 7.94 (2H, d), 7.59 (1H, t), 7.39 (2H, d), 7.28 (1H, d), 6.65 (1H, d), 4.36 (2H, t), 3.02 (2H, t), 2.54 (2H, t), 2.00 (2H, m), 1.82 (2H, m), 1.04 (3H, t).[2949] <1>H-NMR (CDCl<3>) δ 7.94 (2H, d), 7.59 (1H, t), 7.39 (2H, d), 7.28 (1H, d), 6.65 (1H, d), 4.36 (2H, t), 3.02 (2H, t), 2.54 (2H, t), 2.00 (2H, m), 1.82 (2H, m), 1.04 (3H, t).

[2951] Primer 133: 4-[4-(6-ciklopentilsulfanil-piridin-2-il)-fenilsulfanil]-buterna kiselina[2951] Example 133: 4-[4-(6-cyclopentylsulfanyl-pyridin-2-yl)-phenylsulfanyl]-butyric acid

[2952][2952]

[2954] [2954]

[2957] Etil estar 4-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.06 g, 0.17 mmol) dobijen u primeru pripreme 159 i 2-bromo-6-ciklopentilsulfanil-piridin (0.049 g, 0.19 mmol) dobijen u primeru pripreme 234 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.02 g, 28%).[2957] 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.06 g, 0.17 mmol) obtained in Preparation Example 159 and 2-bromo-6-cyclopentylsulfanyl-pyridine (0.049 g, 0.19 mmol) obtained in Preparation Example 234 were used. to react in the same manner as in steps A and B of Example 1 to give the title compound (0.02 g, 28%).

[2958] <1>H-NMR (CDCl<3>) δ 7.95 (2H, d), 7.50 (1H, t), 7.40-7.38 (3H, m), 7.05 (1H, d), 4.17 (1H, m), 3.03 (2H, t), 2.55 (2H, t), 2.24 (2H, m), 2.00 (2H, m), 1.82-1.63 (6H, m).[2958] <1>H-NMR (CDCl<3>) δ 7.95 (2H, d), 7.50 (1H, t), 7.40-7.38 (3H, m), 7.05 (1H, d), 4.17 (1H, m), 3.03 (2H, t), 2.55 (2H, t), 2.24 (2H, m), 2.00 (2H, m), 1.82-1.63 (6H, m).

[2960] Primer 134: 4-(3'-ciklobutoksi-3,5-difluoro-bifenil-4-ilsulfanil)-buterna kiselina[2960] Example 134: 4-(3'-cyclobutoxy-3,5-difluoro-biphenyl-4-ylsulfanyl)-butyric acid

[2961][2961]

[2963] [2963]

[2966] 3'-ciklobutoksi-3,4,5-trifluoro-bifenil (0.02 g, 0.07 mmol) dobijen u primeru pripreme 163, Cs<2>CO<3>(0.022 g, 0.07 mmol) i etil estar 4-merkapto-buterne kiseline (0.01 g, 0.07 mmol) dobijen u primeru pripreme 161 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 137 da bi se dobilo naslovno jedinjenje (0.001 g, 4%).[2966] 3'-cyclobutoxy-3,4,5-trifluoro-biphenyl (0.02 g, 0.07 mmol) obtained in Preparation Example 163, Cs<2>CO<3> (0.022 g, 0.07 mmol) and 4-mercapto-butyric acid ethyl ester (0.01 g, 0.07 mmol) obtained in Preparation Example 161 were used to react in the same manner as in steps A and B of Example 137 to give the title compound (0.001 g, 4%).

[2967] <1>H-NMR (CDCl<3>) δ 7.32 (1H, t), 7.13 (2H, d), 7.12 (1H, m), 6.96 (1H, s), 6.84 (1H, m), 4.68 (1H, m), 2.94 (2H, t), 2.55 (2H, t), 2.47 (2H, m), 2.19 (2H, m), 1.87 (3H, m), 1.71 (1H, m).[2967] <1>H-NMR (CDCl<3>) δ 7.32 (1H, t), 7.13 (2H, d), 7.12 (1H, m), 6.96 (1H, s), 6.84 (1H, m), 4.68 (1H, m), 2.94 (2H, t), 2.55 (2H, t), 2.47 (2H, m), 2.19 (2H, m), 1.87 (3H, m), 1.71 (1H, m).

[2969] Primer 135: 4-(3,5-difluoro-3'-izopropoksi-bifenil-4-ilsulfanil)-buterna kiselina[2969] Example 135: 4-(3,5-difluoro-3'-isopropoxy-biphenyl-4-ylsulfanyl)-butyric acid

[2970][2970]

[2972] [2972]

[2975] 3,4,5-trifluoro-3'-izopropoksi-bifenil (0.06 g, 0.23 mmol) dobijen u primeru pripreme 164, Cs<2>CO<3>(0.074 g, 0.23 mmol) i etil estar 4-merkapto-buterne kiseline (0.034 g, 0.23 mmol) dobijen u primeru pripreme 161 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 137 da bi se dobilo naslovno jedinjenje (0.011 g, 13%).[2975] 3,4,5-trifluoro-3'-isopropoxy-biphenyl (0.06 g, 0.23 mmol) obtained in Preparation Example 164, Cs<2>CO<3> (0.074 g, 0.23 mmol) and 4-mercapto-butyric acid ethyl ester (0.034 g, 0.23 mmol) obtained in Preparation Example 161 were used to make reacted in the same manner as in steps A and B of Example 137 to give the title compound (0.011 g, 13%).

[2976] <1>H-NMR (CDCl<3>) δ 7.33 (1H, t), 7.13 (2H, d), 7.09 (1H, m), 7.04 (1H, s), 6.92 (1H, m), 4.60 (1H, m), 2.94 (2H, t), 2.55 (2H, t), 1.87 (2H, m), 1.35 (6H, d).[2976] <1>H-NMR (CDCl<3>) δ 7.33 (1H, t), 7.13 (2H, d), 7.09 (1H, m), 7.04 (1H, s), 6.92 (1H, m), 4.60 (1H, m), 2.94 (2H, t), 2.55 (2H, t), 1.87 (2H, m), 1.35 (6H, d).

[2978] Primer 136: 4-[2,6-difluoro-4-(6-propoksi-piridin-2-il)-fenilsulfanil]-buterna kiselina[2978] Example 136: 4-[2,6-difluoro-4-(6-propoxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid

[2979][2979]

[2981] [2981]

[2982] 2-propoksi-6-(3,4,5-trifluoro-fenil)-piridin (0.02 g, 0.08 mmol) dobijen u primeru pripreme 166, Cs<2>CO<3>(0.028 g, 0.08 mmol) i etil estar 4-merkapto-buterne kiseline (0.01 g, 0.08 mmol) dobijen u primeru pripreme 161 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 137 da bi se dobilo naslovno jedinjenje (0.008 g, 24%).[2982] 2-Propoxy-6-(3,4,5-trifluoro-phenyl)-pyridine (0.02 g, 0.08 mmol) obtained in Preparation Example 166, Cs<2>CO<3> (0.028 g, 0.08 mmol) and 4-mercapto-butyric acid ethyl ester (0.01 g, 0.08 mmol) obtained in Preparation Example 161 were used to make reacted in the same manner as in steps A and B of Example 137 to give the title compound (0.008 g, 24%).

[2983] <1>H-NMR (CDCl<3>) δ 7.63-7.59 (3H, m), 7.27 (1H, d), 6.71 (1H, d), 4.35 (2H, t), 2.96 (2H, t), 2.54 (2H, t), 1.88-1.82 (4H, m), 1.05 (3H, t).[2983] <1>H-NMR (CDCl<3>) δ 7.63-7.59 (3H, m), 7.27 (1H, d), 6.71 (1H, d), 4.35 (2H, t), 2.96 (2H, t), 2.54 (2H, t), 1.88-1.82 (4H, m), 1.05 (3H, t).

[2985] Primer 137: 4-[2,6-difluoro-4-(6-izopropoksi-piridin-2-il)-fenilsulfanil]-buterna kiselina[2985] Example 137: 4-[2,6-difluoro-4-(6-isopropoxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid

[2986][2986]

[2988] [2988]

[2991] Faza A: etil estar 4-[2,6-difluoro-4-(6-izopropoksi-piridin-2-il)-fenilsulfanil]-buterne kiseline [1162] 2-izopropoksi-6-(3,4,5-trifluoro-fenil)-piridin (0.02 g, 0.07 mmol) dobijen u primeru pripreme 167 je rastvoren u 1 mL DMF-a, i dodati su Cs<2>CO<3>(0.024 g, 0.07 mmol) i etil estar 4-merkapto-buterne kiseline (0.011 g, 0.07 mmol) dobijen u primeru pripreme 161. Proizvod je mešan 4 sata na 65°C.[2991] Phase A: 4-[2,6-difluoro-4-(6-isopropoxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid ethyl ester [1162] 2-Isopropoxy-6-(3,4,5-trifluoro-phenyl)-pyridine (0.02 g, 0.07 mmol) obtained in Preparation Example 167 was dissolved in 1 mL of DMF, and added. Cs<2>CO<3> (0.024 g, 0.07 mmol) and 4-mercapto-butyric acid ethyl ester (0.011 g, 0.07 mmol) obtained in preparation example 161. The product was stirred for 4 hours at 65°C.

[2992] Reakcionom rastvoru je dodata voda i ekstrahovan je sa EtOAc. Odvojeni organski sloj je osušen sa MgSO<4>i prečišćen hromatografijom na koloni da bi se dobilo naslovno jedinjenje (0.017 g, 58 %).[2992] Water was added to the reaction solution and extracted with EtOAc. The separated organic layer was dried with MgSO4 and purified by column chromatography to give the title compound (0.017 g, 58 %).

[2994] Faza B: 4-[2,6-difluoro-4-(6-izopropoksi-piridin-2-il)-fenilsulfanil]-buterna kiselina[2994] Phase B: 4-[2,6-difluoro-4-(6-isopropoxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid

[2995] Etil estar 4-[2,6-difluoro-4-(6-izopropoksi-piridin-2-il)-fenilsulfanil]-buterne kiseline (0.017 g, 0.04 mmol) dobijen u fazi A je izreagovan na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.011 g, 73%).[2995] 4-[2,6-difluoro-4-(6-isopropoxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.017 g, 0.04 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to give the title compound (0.011 g, 73%).

[2996] <1>H-NMR (CDCl<3>) δ 7.63-7.57 (3H, m), 7.23 (1H, d), 6.67 (1H, d), 5.44 (1H, m), 2.97 (2H, t), 2.55 (2H, t), 1.88 (2H, m), 1.40 (6H, d).[2996] <1>H-NMR (CDCl<3>) δ 7.63-7.57 (3H, m), 7.23 (1H, d), 6.67 (1H, d), 5.44 (1H, m), 2.97 (2H, t), 2.55 (2H, t), 1.88 (2H, m), 1.40 (6H, d).

[2998] Primer 138: 4-[2,6-difluoro-4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-buterna kiselina[2998] Example 138: 4-[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-butyric acid

[2999][2999]

[3001] [3001]

[3004] Etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (1.22 g, 3.16 mmol) dobijen u primeru pripreme 170 i 3-jodo-2-izopropoksi-piridin (1.24 g, 4.74 mmol) dobijen u primeru pripreme 37 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.78 g, 67%).[3004] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (1.22 g, 3.16 mmol) obtained in preparation example 170 and 3-iodo-2-isopropoxy-pyridine (1.24 g, 4.74 mmol) obtained in preparation example 37 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.78 g, 67%).

[3005] <1>H-NMR (CDCl<3>) δ 8.15 (1H, m), 7.60 (1H, m), 7.19 (2H, d), 6.93 (1H, m), 5.40 (1H, m), 2.96 (2H, t), 2.56 (2H, t), 1.90 (2H, m), 1.36 (6H, d).[3005] <1>H-NMR (CDCl<3>) δ 8.15 (1H, m), 7.60 (1H, m), 7.19 (2H, d), 6.93 (1H, m), 5.40 (1H, m), 2.96 (2H, t), 2.56 (2H, t), 1.90 (2H, m), 1.36 (6H, d).

[3007] Primer 139: 4-[2,6-difluoro-4-(2-propoksi-piridin-3-il)-fenilsulfanil]-buterna kiselina[3007] Example 139: 4-[2,6-difluoro-4-(2-propoxy-pyridin-3-yl)-phenylsulfanyl]-butyric acid

[3008][3008]

[3010] [3010]

[3013] 2-propoksi-3-(3,4,5-trifluoro-fenil)-piridin (0.02 g, 0.08 mmol) dobijen u primeru pripreme 171, Cs<2>CO<3>(0.027 g, 0.08 mmol) i etil estar 4-merkapto-buterne kiseline (0.012 g, 0.08 mmol) dobijen u primeru pripreme 161 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 137 da bi se dobilo naslovno jedinjenje (0.009 g, 30%).[3013] 2-Propoxy-3-(3,4,5-trifluoro-phenyl)-pyridine (0.02 g, 0.08 mmol) obtained in Preparation Example 171, Cs<2>CO<3> (0.027 g, 0.08 mmol) and 4-mercapto-butyric acid ethyl ester (0.012 g, 0.08 mmol) obtained in Preparation Example 161 were used to would react in the same manner as in steps A and B of Example 137 to give the title compound (0.009 g, 30%).

[3014] <1>H-NMR (CDCl<3>) δ 8.16 (1H, m), 7.60 (1H, m), 7.20 (2H, d), 6.95 (1H, m), 4.32 (2H, t), 2.96 (2H, t), 2.54 (2H, t), 1.89 (2H, m), 1.80 (2H, m), 1.00 (3H, t).[3014] <1>H-NMR (CDCl<3>) δ 8.16 (1H, m), 7.60 (1H, m), 7.20 (2H, d), 6.95 (1H, m), 4.32 (2H, t), 2.96 (2H, t), 2.54 (2H, t), 1.89 (2H, m), 1.80 (2H, m), 1.00 (3H, t).

[3016] Primer 140: 4-[2,6-difluoro-4-(6-izopropilsulfanil-piridin-2-il)-fenil sulfanil]-buterna kiselina [1171][3016] Example 140: 4-[2,6-difluoro-4-(6-isopropylsulfanyl-pyridin-2-yl)-phenyl sulfanyl]-butyric acid [1171]

[3018] [3018]

[3021] 2-izopropilsulfanil-6-(3,4,5-trifluoro-fenil)-piridin (0.035 g, 0.12 mmol) dobijen u primeru pripreme 172, Cs<2>CO<3>(0.04 g, 0.12 mmol) i etil estar 4-merkapto-buterne kiseline (0.018 g, 0.12 mmol) dobijen u primeru pripreme 161 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 137 da bi se dobilo naslovno jedinjenje (0.022 g, 46%).[3021] 2-isopropylsulfanyl-6-(3,4,5-trifluoro-phenyl)-pyridine (0.035 g, 0.12 mmol) obtained in preparation example 172, Cs<2>CO<3> (0.04 g, 0.12 mmol) and 4-mercapto-butyric acid ethyl ester (0.018 g, 0.12 mmol) obtained in preparation example 161 were used to react in the same manner as in steps A and B of Example 137 to give the title compound (0.022 g, 46%).

[3022] <1>H-NMR (CDCl<3>) δ 7.62-7.53 (3H, m), 7.37 (1H, d), 7.13 (1H, d), 4.14 (1H, m), 2.98 (2H, t), 2.56 (2H, t), 1.89 (2H, m), 1.45 (6H, d).[3022] <1>H-NMR (CDCl<3>) δ 7.62-7.53 (3H, m), 7.37 (1H, d), 7.13 (1H, d), 4.14 (1H, m), 2.98 (2H, t), 2.56 (2H, t), 1.89 (2H, m), 1.45 (6H, d).

[3023] Primer 141: 4-[2,6-difluoro-4-(6-propilsulfanil-piridin-2-il)-fenil sulfanil]-buterna kiselina[3023] Example 141: 4-[2,6-difluoro-4-(6-propylsulfanyl-pyridin-2-yl)-phenyl sulfanyl]-butyric acid

[3024][3024]

[3026] [3026]

[3029] 2-propilsulfanil-6-(3,4,5-trifluoro-fenil)-piridin (0.03 g, 0.11 mmol) dobijen u primeru pripreme 173, Cs<2>CO<3>(0.035 g, 0.11 mmol) i etil estar 4-merkapto-buterne kiseline (0.016 g, 0.11 mmol) dobijen u primeru pripreme 161 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 137 da bi se dobilo naslovno jedinjenje (0.024 g, 57%).[3029] 2-Propylsulfanyl-6-(3,4,5-trifluoro-phenyl)-pyridine (0.03 g, 0.11 mmol) obtained in preparation example 173, Cs<2>CO<3> (0.035 g, 0.11 mmol) and 4-mercapto-butyric acid ethyl ester (0.016 g, 0.11 mmol) obtained in preparation example 161 were used to react in the same manner as in steps A and B of Example 137 to give the title compound (0.024 g, 57%).

[3030] <1>H-NMR (CDCl<3>) δ 7.62-7.53 (3H, m), 7.37 (1H, d), 7.16 (1H, d), 3.24 (2H, t), 2.98 (2H, t), 2.56 (2H, t), 1.92-1.77 (4H, m), 1.09 (3H, t).[3030] <1>H-NMR (CDCl<3>) δ 7.62-7.53 (3H, m), 7.37 (1H, d), 7.16 (1H, d), 3.24 (2H, t), 2.98 (2H, t), 2.56 (2H, t), 1.92-1.77 (4H, m), 1.09 (3H, t).

[3032] Primer 142: 4-[4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-difluoro-fenil sulfanil]-buterna kiselina [1177][3032] Example 142: 4-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl sulfanyl]-butyric acid [1177]

[3034] [3034]

[3037] 2-ciklobutilsulfanil-3-(3,4,5-trifluoro-fenil)-piridin (0.056 g, 0.19 mmol) dobijen u primeru pripreme 174, Cs<2>CO<3>(0.093 g, 0.19 mmol) i etil estar 4-merkapto-buterne kiseline (0.028 g, 0.19 mmol) iz primera pripreme 161 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 137 da bi se dobilo naslovno jedinjenje (0.03 g, 40%).[3037] 2-cyclobutylsulfanyl-3-(3,4,5-trifluoro-phenyl)-pyridine (0.056 g, 0.19 mmol) obtained in preparation example 174, Cs<2>CO<3> (0.093 g, 0.19 mmol) and 4-mercapto-butyric acid ethyl ester (0.028 g, 0.19 mmol) from preparation example 161 are used to react in the same manner as in steps A and B of Example 137 to give the title compound (0.03 g, 40%).

[3038] <1>H-NMR (CDCl<3>) δ 8.42 (1H, m), 7.34 (1H, m), 7.02 (3H, m), 4.42 (1H, m), 2.98 (2H, t), 2.58-2.48 (4H, m), 2.10-1.89 (6H, m).[3038] <1>H-NMR (CDCl<3>) δ 8.42 (1H, m), 7.34 (1H, m), 7.02 (3H, m), 4.42 (1H, m), 2.98 (2H, t), 2.58-2.48 (4H, m), 2.10-1.89 (6H, m).

[3040] Primer 143: 4-[4-(2-ciklobutoksi-piridin-3-il)-fenilsulfanil]-buterna kiselina[3040] Example 143: 4-[4-(2-cyclobutoxy-pyridin-3-yl)-phenylsulfanyl]-butyric acid

[3041][3041]

[3043] [3043]

[3046] Etil estar 4-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.018 g, 0.05 mmol) dobijen u primeru pripreme 159 i 2-ciklobutoksi-3-jodo-piridin (0.016 g, 0.06 mmol) dobijen u primeru pripreme 200 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.004 g, 23%).[3046] 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.018 g, 0.05 mmol) obtained in Preparation Example 159 and 2-cyclobutoxy-3-iodo-pyridine (0.016 g, 0.06 mmol) obtained in Preparation Example 200 were used to would react in the same manner as in steps A and B of Example 1 to give the title compound (0.004 g, 23%).

[3047] <1>H-NMR (CDCl<3>) δ 8.09 (1H, m), 7.58 (1H, m), 7.52 (2H, d), 7.36 (2H, d), 6.91 (1H, m), 5.26 (1H, m), 3.02 (2H, t), 2.56-2.42 (4H, m), 2.15-1.99 (4H, m), 1.81 (1H, m), 1.67 (1H, m).[3047] <1>H-NMR (CDCl<3>) δ 8.09 (1H, m), 7.58 (1H, m), 7.52 (2H, d), 7.36 (2H, d), 6.91 (1H, m), 5.26 (1H, m), 3.02 (2H, t), 2.56-2.42 (4H, m), 2.15-1.99 (4H, m), 1.81 (1H, m), 1.67 (1H, m).

[3049] Primer 144: 4-[4-(2-ciklobutoksi-piridin-3-il)-2,6-difluoro-fenil sulfanil]-buterna kiselina[3049] Example 144: 4-[4-(2-cyclobutoxy-pyridin-3-yl)-2,6-difluoro-phenyl sulfanyl]-butyric acid

[3050][3050]

[3052] [3052]

[3055] 2-ciklobutoksi-3-(3,4,5-trifluoro-fenil)-piridin (0.01 g, 0.03 mmol) dobijen u primeru pripreme 175, Cs<2>CO<3>(0.012 g, 0.03 mmol) i etil estar 4-merkapto-buterne kiseline (0.005 g, 0.03 mmol) dobijen u primeru pripreme 161 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 137 da bi se dobilo naslovno jedinjenje (0.002 g, 17%).[3055] 2-Cyclobutoxy-3-(3,4,5-trifluoro-phenyl)-pyridine (0.01 g, 0.03 mmol) obtained in Preparation Example 175, Cs<2>CO<3> (0.012 g, 0.03 mmol) and 4-mercapto-butyric acid ethyl ester (0.005 g, 0.03 mmol) obtained in Preparation Example 161 were used. to react in the same manner as in steps A and B of Example 137 to give the title compound (0.002 g, 17%).

[3056] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.60 (1H, m), 7.21 (2H, d), 6.95 (1H, m), 5.27 (1H, m), 2.97 (2H, t), 2.56-2.42 (4H, m), 2.12 (2H, m), 1.91-1.81 (3H, m), 1.69 (1H, m).[3056] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.60 (1H, m), 7.21 (2H, d), 6.95 (1H, m), 5.27 (1H, m), 2.97 (2H, t), 2.56-2.42 (4H, m), 2.12 (2H, m), 1.91-1.81 (3H, m), 1.69 (1H, m).

[3058] Primer 145: 4-[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenil sulfanil]-buterna kiselina[3058] Example 145: 4-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenyl sulfanyl]-butyric acid

[3059][3059]

[3061] [3061]

[3064] Etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.063 g, 0.16 mmol) dobijen u primeru pripreme 170 i 2-ciklopentoksi-3-jodo-piridin (0.052 g, 0.18 mmol) dobijen u primeru pripreme 38 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.025 g, 39%).[3064] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.063 g, 0.16 mmol) obtained in preparation example 170 and 2-cyclopentoxy-3-iodo-pyridine (0.052 g, 0.18 mmol) obtained in preparation example 38 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.025 g, 39%).

[3065] <1>H-NMR (CDCl<3>) δ 8.17 (1H, m), 7.58 (1H, m), 7.17 (2H, d), 6.92 (1H, m), 5.51 (1H, m), 2.96 (2H, t), 2.55 (2H, m), 1.98-1.87 (4H, m), 1.81-1.73 (4H, m), 1.63 (2H, m).[3065] <1>H-NMR (CDCl<3>) δ 8.17 (1H, m), 7.58 (1H, m), 7.17 (2H, d), 6.92 (1H, m), 5.51 (1H, m), 2.96 (2H, t), 2.55 (2H, m), 1.98-1.87 (4H, m), 1.81-1.73 (4H, m), 1.63 (2H, m).

[3067] Primer 146: 4-[2,6-difluoro-4-(2-izopropilsulfanil-piridin-3-il)-fenil sulfanil]-buterna kiselina [1189][3067] Example 146: 4-[2,6-difluoro-4-(2-isopropylsulfanyl-pyridin-3-yl)-phenyl sulfanyl]-butyric acid [1189]

[3069] [3069]

[3070] Etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.02 g, 0.05 mmol) dobijen u primeru pripreme 170 i 3-jodo-2-izopropilsulfanil-piridin (0.015 g, 0.054 mmol) dobijen u primeru pripreme 226 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.007 g, 36%).[3070] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.02 g, 0.05 mmol) obtained in preparation example 170 and 3-iodo-2-isopropylsulfanyl-pyridine (0.015 g, 0.054 mmol) obtained in example Preparation 226 was used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.007 g, 36%).

[3071] <1>H-NMR (CDCl<3>) δ 8.45 (1H, m), 7.36 (1H, m), 7.04-7.00 (3H, m), 4.06 (1H, m), 2.98 (2H, t), 2.57 (2H, t), 1.91 (2H, m), 1.34 (6H, d).[3071] <1>H-NMR (CDCl<3>) δ 8.45 (1H, m), 7.36 (1H, m), 7.04-7.00 (3H, m), 4.06 (1H, m), 2.98 (2H, t), 2.57 (2H, t), 1.91 (2H, m), 1.34 (6H, d).

[3073] Primer 147: 4-[4-(2-ciklopentilsulfanil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina [1192][3073] Example 147: 4-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid [1192]

[3075] [3075]

[3078] 2-ciklopentilsulfanil-3-(3,4,5-trifluoro-fenil)-piridin (0.02 g, 0.06 mmol) dobijen u primeru pripreme 176, Cs<2>CO<3>(0.02 g, 0.06 mmol) i etil estar 4-merkapto-buterne kiseline (0.01 g, 0.06 mmol) dobijen u primeru pripreme 161 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 137 da bi se dobilo naslovno jedinjenje (0.007 g, 26%).[3078] 2-cyclopentylsulfanyl-3-(3,4,5-trifluoro-phenyl)-pyridine (0.02 g, 0.06 mmol) obtained in preparation example 176, Cs<2>CO<3> (0.02 g, 0.06 mmol) and 4-mercapto-butyric acid ethyl ester (0.01 g, 0.06 mmol) obtained in preparation example 161 were used to react in the same manner as in steps A and B of Example 137 to give the title compound (0.007 g, 26%).

[3079] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.34 (1H, m), 7.03-7.01 (3H, m), 4.09 (1H, m), 2.98 (2H, t), 2.57 (2H, t), 2.18 (2H, m), 1.91 (2H, m), 1.72-1.52 (6H, m).[3079] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.34 (1H, m), 7.03-7.01 (3H, m), 4.09 (1H, m), 2.98 (2H, t), 2.57 (2H, t), 2.18 (2H, m), 1.91 (2H, m), 1.72-1.52 (6H, m).

[3081] Primer 148: 4-[4-(2-izopropilsulfanil-piridin-3-il)-fenilsulfanil]-buterna kiselina[3081] Example 148: 4-[4-(2-isopropylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-butyric acid

[3082][3082]

[3084] [3084]

[3087] Etil estar 4-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 159 i 3-jodo-2-izopropilsulfanil-piridin (0.044 g, 0.16 mmol) dobijen u primeru pripreme 226 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.013 g, 27%).[3087] 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 159 and 3-iodo-2-isopropylsulfanyl-pyridine (0.044 g, 0.16 mmol) obtained in Preparation Example 226 were used. to react in the same manner as in steps A and B of Example 1 to give the title compound (0.013 g, 27%).

[3088] <1>H-NMR (CDCl<3>) δ 8.41 (1H, m), 7.39-7.32 (5H, m), 7.02 (1H, m), 4.04 (1H, m), 3.04 (2H, t), 2.55 (2H, t), 2.03 (2H, m), 1.34 (6H, d).[3088] <1>H-NMR (CDCl<3>) δ 8.41 (1H, m), 7.39-7.32 (5H, m), 7.02 (1H, m), 4.04 (1H, m), 3.04 (2H, t), 2.55 (2H, t), 2.03 (2H, m), 1.34 (6H, d).

[3089] Primer 149: 4-[4-(2-ciklopentilsulfanil-piridin-3-il)-fenilsulfanil]-buterna kiselina[3089] Example 149: 4-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-butyric acid

[3090][3090]

[3092] [3092]

[3095] Etil estar 4-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 159 i 2-ciklopentilsulfanil-3-jodo-piridin (0.048 g, 0.16 mmol) dobijen u primeru pripreme 39 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.011 g, 20%).[3095] 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 159 and 2-cyclopentylsulfanyl-3-iodo-pyridine (0.048 g, 0.16 mmol) obtained in Preparation Example 39 were used. to react in the same manner as in steps A and B of Example 1 to give the title compound (0.011 g, 20%).

[3096] <1>H-NMR (CDCl<3>) δ 8.41 (1H, m), 7.39-7.32 (5H, m), 7.02 (1H, m), 4.04 (1H, m), 3.03 (2H, t), 2.55 (2H, t), 2.18 (2H, m), 2.02 (2H, m), 1.72-1.52 (6H, m).[3096] <1>H-NMR (CDCl<3>) δ 8.41 (1H, m), 7.39-7.32 (5H, m), 7.02 (1H, m), 4.04 (1H, m), 3.03 (2H, t), 2.55 (2H, t), 2.18 (2H, m), 2.02 (2H, m), 1.72-1.52 (6H, m).

[3098] Primer 150: 4-[2-fluoro-4-(6-izopropoksi-piridin-2-il)-fenilsulfanil]-buterna kiselina[3098] Example 150: 4-[2-fluoro-4-(6-isopropoxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid

[3099][3099]

[3101] [3101]

[3104] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.13 mmol) dobijen u primeru pripreme 180 i 2-bromo-6-izopropoksi-piridin (0.032 g, 0.15 mmol) dobijen u primeru pripreme 228 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.014 g, 29%).[3104] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.13 mmol) obtained in preparation example 180 and 2-bromo-6-isopropoxy-pyridine (0.032 g, 0.15 mmol) obtained in preparation example 228 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.014 g, 29%).

[3105] <1>H-NMR (CDCl<3>) δ 7.73-7.71 (2H, m), 7.59 (1H, t), 7.42 (1H, t), 7.25 (1H, m), 6.64 (1H, d), 5.45 (1H, m), 3.00 (2H, t), 2.54 (2H, t), 1.95 (2H, m), 1.38 (6H, d).[3105] <1>H-NMR (CDCl<3>) δ 7.73-7.71 (2H, m), 7.59 (1H, t), 7.42 (1H, t), 7.25 (1H, m), 6.64 (1H, d), 5.45 (1H, m), 3.00 (2H, t), 2.54 (2H, t), 1.95 (2H, m), 1.38 (6H, d).

[3107] Primer 151: 4-[4-(2-ciklopentiloksi-piridin-3-il)-2-fluoro-fenilsulfanil] - buterna kiselina[3107] Example 151: 4-[4-(2-cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric acid

[3108][3108]

[3110] [3110]

[3113] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.13 mmol) dobijen u primeru pripreme 180 i 2-ciklopentoksi-3-jodo-piridin (0.04 g, 0.15 mmol) dobijen u primeru pripreme 38 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.027 g, 54%).[3113] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.13 mmol) obtained in Preparation Example 180 and 2-cyclopentoxy-3-iodo-pyridine (0.04 g, 0.15 mmol) obtained in Preparation Example 38 were used. to react in the same manner as in steps A and B of Example 1 to give the title compound (0.027 g, 54%).

[3114] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.57 (1H, m), 7.38 (1H, t), 7.29-7.27 (2H, m), 6.91 (1H, m), 5.50 (1H, m), 3.00 (2H, t), 2.55 (2H, t), 1.98-1.93 (4H, m), 1.86-1.59 (6H, m).[3114] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.57 (1H, m), 7.38 (1H, t), 7.29-7.27 (2H, m), 6.91 (1H, m), 5.50 (1H, m), 3.00 (2H, t), 2.55 (2H, t), 1.98-1.93 (4H, m), 1.86-1.59 (6H, m).

[3116] Primer 152: 4-[4-(2-ciklobutilsulfanil-piridin-3-il)-2-fluoro-fenil sulfanil]-buterna kiselina[3116] Example 152: 4-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2-fluoro-phenyl sulfanyl]-butyric acid

[3117][3117]

[3119] [3119]

[3122] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.13 mmol) dobijen u primeru pripreme 180 i 2-ciklobutilsulfanil-3-jodo-piridin (0.04 g, 0.15 mmol) dobijen u primeru pripreme 44 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.032 g, 62%).[3122] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.13 mmol) obtained in Preparation Example 180 and 2-cyclobutylsulfanyl-3-iodo-pyridine (0.04 g, 0.15 mmol) obtained in Preparation Example 44 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.032 g, 62%).

[3123] <1>H-NMR (CDCl<3>) δ 8.40 (1H, m), 7.41 (1H, t), 7.33 (1H, m), 7.15 (2H, m), 7.02 (1H, m), 4.42 (1H, m), 3.02 (2H, t), 2.57 (2H, t), 2.55 (2H, m), 2.10-1.97 (6H, m).[3123] <1>H-NMR (CDCl<3>) δ 8.40 (1H, m), 7.41 (1H, t), 7.33 (1H, m), 7.15 (2H, m), 7.02 (1H, m), 4.42 (1H, m), 3.02 (2H, t), 2.57 (2H, t), 2.55 (2H, m), 2.10-1.97 (6H, m).

[3125] Primer 153: 4-[4-(2-ciklobutilsulfanil-piridin-3-il)-fenilsulfanil]-buterna kiselina[3125] Example 153: 4-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-butyric acid

[3126][3126]

[3128] [3128]

[3131] Etil estar 4-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 159 i 2-ciklobutilsulfanil-3-jodo-piridin (0.046 g, 0.16 mmol) dobijen u primeru pripreme 44 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.015 g, 29%).[3131] 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 159 and 2-cyclobutylsulfanyl-3-iodo-pyridine (0.046 g, 0.16 mmol) obtained in Preparation Example 44 were used to would react in the same way as in steps A and B of Example 1 to give the title compound (0.015 g, 29%).

[3132] <1>H-NMR (CDCl<3>) δ 8.38 (1H, m), 7.37-7.34 (5H, m), 7.02 (1H, m), 4.41 (1H, m), 3.03 (2H, t), 2.57 (2H, t), 2.54 (2H, m), 2.10-1.97 (6H, m).[3132] <1>H-NMR (CDCl<3>) δ 8.38 (1H, m), 7.37-7.34 (5H, m), 7.02 (1H, m), 4.41 (1H, m), 3.03 (2H, t), 2.57 (2H, t), 2.54 (2H, m), 2.10-1.97 (6H, m).

[3134] Primer 154: 4-[4-(6-ciklobutoksi-piridin-2-il)-2,6-difluoro-fenil sulfanil]-buterna kiselina[3134] Example 154: 4-[4-(6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenyl sulfanyl]-butyric acid

[3135][3135]

[3137] [3137]

[3138] 2-ciklobutoksi-6-(3,4,5-trifluoro-fenil)-piridin (0.03 g, 0.11 mmol) dobijen u primeru pripreme 181, Cs<2>CO<3>(0.035 g, 0.11 mmol) i etil estar 4-merkapto-buterne kiseline (0.016 g, 0.11 mmol) dobijen u primeru pripreme 161 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 137 da bi se dobilo naslovno jedinjenje (0.011 g, 27%).[3138] 2-Cyclobutoxy-6-(3,4,5-trifluoro-phenyl)-pyridine (0.03 g, 0.11 mmol) obtained in Preparation Example 181, Cs<2>CO<3> (0.035 g, 0.11 mmol) and 4-mercapto-butyric acid ethyl ester (0.016 g, 0.11 mmol) obtained in Preparation Example 161 were used. to react in the same manner as in steps A and B of Example 137 to give the title compound (0.011 g, 27%).

[3139] <1>H-NMR (CDCl<3>) δ 7.64-7.57 (3H, m), 7.27 (1H, d), 6.69 (1H, d), 5.26 (1H, m), 2.96 (2H, t), 2.57-2.51 (4H, m), 2.18 (2H, m), 1.87 (3H, m), 1.76 (1H, m).[3139] <1>H-NMR (CDCl<3>) δ 7.64-7.57 (3H, m), 7.27 (1H, d), 6.69 (1H, d), 5.26 (1H, m), 2.96 (2H, t), 2.57-2.51 (4H, m), 2.18 (2H, m), 1.87 (3H, m), 1.76 (1H, m).

[3141] Primer 155: 4-[4-(6-ciklopentiloksi-piridin-2-il)-2,6-difluoro-fenil sulfanil]-buterna kiselina[3141] Example 155: 4-[4-(6-cyclopentyloxy-pyridin-2-yl)-2,6-difluoro-phenyl sulfanyl]-butyric acid

[3142][3142]

[3144] [3144]

[3147] 2-ciklopentiloksi-6-(3,4,5-trifluoro-fenil)-piridin (0.035 g, 0.12 mmol) dobijen u primeru pripreme 182, Cs<2>CO<3>(0.039 g, 0.12 mmol) i etil estar 4-merkapto-buterne kiseline (0.018 g, 0.12 mmol) dobijen u primeru pripreme 161 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 137 da bi se dobilo naslovno jedinjenje (0.016 g, 34%).[3147] 2-cyclopentyloxy-6-(3,4,5-trifluoro-phenyl)-pyridine (0.035 g, 0.12 mmol) obtained in preparation example 182, Cs<2>CO<3> (0.039 g, 0.12 mmol) and 4-mercapto-butyric acid ethyl ester (0.018 g, 0.12 mmol) obtained in preparation example 161 were used to react in the same manner as in steps A and B of Example 137 to give the title compound (0.016 g, 34%).

[3148] <1>H-NMR (CDCl<3>) δ 7.62-7.58 (3H, m), 7.24 (1H, d), 6.67 (1H, d), 5.50 (1H, m), 2.96 (2H, t), 2.54 (2H, t), 2.03 (2H, m), 1.89-1.78 (6H, m), 1.65 (2H, m).[3148] <1>H-NMR (CDCl<3>) δ 7.62-7.58 (3H, m), 7.24 (1H, d), 6.67 (1H, d), 5.50 (1H, m), 2.96 (2H, t), 2.54 (2H, t), 2.03 (2H, m), 1.89-1.78 (6H, m), 1.65 (2H, m).

[3150] Primer 156: 4-[4-(6-ciklobutilsulfanil-piridin-2-il)-fenilsulfanil]-buterna kiselina[3150] Example 156: 4-[4-(6-cyclobutylsulfanyl-pyridin-2-yl)-phenylsulfanyl]-butyric acid

[3151][3151]

[3153] [3153]

[3156] Etil estar 4-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.011 g, 0.03 mmol) dobijen u primeru pripreme 159 i 2-bromo-6-ciklobutilsulfanil-piridin (0.008 g, 0.03 mmol) dobijen u primeru pripreme 233 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.003 g, 27%).[3156] 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.011 g, 0.03 mmol) obtained in Preparation Example 159 and 2-bromo-6-cyclobutylsulfanyl-pyridine (0.008 g, 0.03 mmol) obtained in Preparation Example 233 were used. to react in the same manner as in steps A and B of Example 1 to give the title compound (0.003 g, 27%).

[3157] <1>H-NMR (CDCl<3>) δ 7.94 (2H, d), 7.49 (1H, t), 7.40-7.37 (3H, m), 7.00 (1H, d), 4.44 (1H, m), 3.03 (2H, t), 2.63-2.53 (4H, m), 2.20-1.98 (6H, m).[3157] <1>H-NMR (CDCl<3>) δ 7.94 (2H, d), 7.49 (1H, t), 7.40-7.37 (3H, m), 7.00 (1H, d), 4.44 (1H, m), 3.03 (2H, t), 2.63-2.53 (4H, m), 2.20-1.98 (6H, m).

[3158] Primer 157: 4-[4-(6-ciklopropilmetoksi-piridin-2-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina [1222][3158] Example 157: 4-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid [1222]

[3160] [3160]

[3163] 2-ciklopropilmetoksi-6-(3,4,5-trifluoro-fenil)-piridin (0.034 g, 0.12 mmol) dobijen u primeru pripreme 183, Cs<2>CO<3>(0.04 g, 0.12 mmol) i etil estar 4-merkapto-buterne kiseline (0.018 g, 0.12 mmol) dobijen u primeru pripreme 161 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 137 da bi se dobilo naslovno jedinjenje (0.012 g, 26%).[3163] 2-cyclopropylmethoxy-6-(3,4,5-trifluoro-phenyl)-pyridine (0.034 g, 0.12 mmol) obtained in preparation example 183, Cs<2>CO<3> (0.04 g, 0.12 mmol) and 4-mercapto-butyric acid ethyl ester (0.018 g, 0.12 mmol) obtained in preparation example 161 were used to react in the same manner as in steps A and B of Example 137 to give the title compound (0.012 g, 26%).

[3164] <1>H-NMR (CDCl<3>) δ 7.65 (1H, t), 7.59 (2H, d), 7.27 (1H, d), 6.76 (1H, d), 4.24 (2H, d), 2.96 (2H, t), 2.54 (2H, t), 1.87 (2H, m), 1.32 (1H, m), 0.64 (2H, m), 0.39 (2H, m).[3164] <1>H-NMR (CDCl<3>) δ 7.65 (1H, t), 7.59 (2H, d), 7.27 (1H, d), 6.76 (1H, d), 4.24 (2H, d), 2.96 (2H, t), 2.54 (2H, t), 1.87 (2H, m), 1.32 (1H, m), 0.64 (2H, m), 0.39 (2H, m).

[3166] Primer 158: 4-[4-(6-ciklobutilsulfanil-piridin-2-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina [1225][3166] Example 158: 4-[4-(6-cyclobutylsulfanyl-pyridin-2-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid [1225]

[3168] [3168]

[3171] 2-ciklobutilsulfanil-6-(3,4,5-trifluoro-fenil)-piridin (0.03 g, 0.1 mmol) dobijen u primeru pripreme 184, Cs<2>CO<3>(0.033 g, 0.1 mmol) i etil estar 4-merkapto-buterne kiseline (0.015 g, 0.1 mmol) dobijen u primeru pripreme 161 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 137 da bi se dobilo naslovno jedinjenje (0.016 g, 40%).[3171] 2-Cyclobutylsulfanyl-6-(3,4,5-trifluoro-phenyl)-pyridine (0.03 g, 0.1 mmol) obtained in Preparation Example 184, Cs<2>CO<3> (0.033 g, 0.1 mmol) and 4-mercapto-butyric acid ethyl ester (0.015 g, 0.1 mmol) obtained in Preparation Example 161 were used to would react in the same manner as in steps A and B of Example 137 to give the title compound (0.016 g, 40%).

[3172] <1>H-NMR (CDCl<3>) δ 7.60 (2H, d), 7.53 (1H, t), 7.35 (1H, d), 7.07 (1H, d), 4.42 (1H, m), 2.98 (2H, t), 2.63-2.53 (4H, m), 2.20-2.10 (4H, m), 1.88 (2H, m).[3172] <1>H-NMR (CDCl<3>) δ 7.60 (2H, d), 7.53 (1H, t), 7.35 (1H, d), 7.07 (1H, d), 4.42 (1H, m), 2.98 (2H, t), 2.63-2.53 (4H, m), 2.20-2.10 (4H, m), 1.88 (2H, m).

[3174] Primer 159: 4-[4-(6-ciklopentilsulfanil-piridin-2-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina [1228][3174] Example 159: 4-[4-(6-cyclopentylsulfanyl-pyridin-2-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid [1228]

[3176] [3176]

[3179] 2-ciklopentilsulfanil-6-(3,4,5-trifluoro-fenil)-piridin (0.04 g, 0.13 mmol) dobijen u primeru pripreme 185, Cs<2>CO<3>(0.044 g, 0.13 mmol) i etil estar 4-merkapto-buterne kiseline (0.02 g, 0.13 mmol) dobijen u primeru pripreme 161 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 137 da bi se dobilo naslovno jedinjenje (0.016 g, 29%).[3179] 2-Cyclopentylsulfanyl-6-(3,4,5-trifluoro-phenyl)-pyridine (0.04 g, 0.13 mmol) obtained in Preparation Example 185, Cs<2>CO<3> (0.044 g, 0.13 mmol) and 4-mercapto-butyric acid ethyl ester (0.02 g, 0.13 mmol) obtained in Preparation Example 161 were used to react in the same manner as in steps A and B of Example 137 to give the title compound (0.016 g, 29%).

[3180] <1>H-NMR (CDCl<3>) δ 7.61 (2H, d), 7.53 (1H, t), 7.35 (1H, d), 7.13 (1H, d), 4.16 (1H, m), 2.97 (2H, t), 2.54 (2H, t), 2.24 (2H, m), 1.89-1.69 (8H, m)[3180] <1>H-NMR (CDCl<3>) δ 7.61 (2H, d), 7.53 (1H, t), 7.35 (1H, d), 7.13 (1H, d), 4.16 (1H, m), 2.97 (2H, t), 2.54 (2H, t), 2.24 (2H, m), 1.89-1.69 (8H, m)

[3182] Primer 160: 4-(2'-ciklopentilamino-3-fluoro-bifenil-4-ilsulfanil)-buterna kiselina[3182] Example 160: 4-(2'-cyclopentylamino-3-fluoro-biphenyl-4-ylsulfanyl)-butyric acid

[3183][3183]

[3185] [3185]

[3188] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.13 mmol) dobijen u primeru pripreme 180 i N-ciklopentil-2-jodo-anilin (0.043 g, 0.15 mmol) dobijen u primeru pripreme 70 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.022 g, 40%).[3188] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.13 mmol) obtained in Preparation Example 180 and N-cyclopentyl-2-iodo-aniline (0.043 g, 0.15 mmol) obtained in Preparation Example 70 were used. to react in the same manner as in steps A and B of Example 1 to give the title compound (0.022 g, 40%).

[3189] <1>H-NMR (CDCl<3>) δ 7.42 (1H, t), 7.23 (1H, m), 7.15 (2H, m), 7.02 (1H, m), 6.72 (2H, m), 3.77 (1H, m), 3.01 (2H, t), 2.56 (2H, t), 1.98 (4H, m), 1.60 (4H, m), 1.37 (2H, m).[3189] <1>H-NMR (CDCl<3>) δ 7.42 (1H, t), 7.23 (1H, m), 7.15 (2H, m), 7.02 (1H, m), 6.72 (2H, m), 3.77 (1H, m), 3.01 (2H, t), 2.56 (2H, t), 1.98 (4H, m), 1.60 (4H, m), 1.37 (2H, m).

[3191] Primer 161: 4-(2'-ciklopentilamino-3,5-difluoro-bifenil-4-ilsulfanil)-buterna kiselina[3191] Example 161: 4-(2'-cyclopentylamino-3,5-difluoro-biphenyl-4-ylsulfanyl)-butyric acid

[3192][3192]

[3194] [3194]

[3197] Etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.06 g, 0.16 mmol) dobijen u primeru pripreme 170 i N-ciklopentil-2-jodo-anilin (0.05 g, 0.17 mmol) dobijen u primeru pripreme 70 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.013 g, 21%).[3197] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.06 g, 0.16 mmol) obtained in Preparation Example 170 and N-cyclopentyl-2-iodo-aniline (0.05 g, 0.17 mmol) obtained in Preparation Example 70 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.013 g, 21%).

[3198] <1>H-NMR (CDCl<3>) δ 7.23 (1H, m), 7.01 (3H, m), 6.72 (2H, m), 3.77 (1H, m), 2.97 (2H, t), 2.56 (2H, t), 2.03-1.89 (4H, m), 1.66-1.58 (4H, m), 1.40 (2H, m).[3198] <1>H-NMR (CDCl<3>) δ 7.23 (1H, m), 7.01 (3H, m), 6.72 (2H, m), 3.77 (1H, m), 2.97 (2H, t), 2.56 (2H, t), 2.03-1.89 (4H, m), 1.66-1.58 (4H, m), 1.40 (2H, m).

[3200] Primer 162: 4-[2'-(ciklopropilmetil-amino)-3,5-difluoro-bifenil-4-ilsulfanil]-buterna kiselina [1237][3200] Example 162: 4-[2'-(cyclopropylmethyl-amino)-3,5-difluoro-biphenyl-4-ylsulfanyl]-butyric acid [1237]

[3202] [3202]

[3203] Etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.054 g, 0.14 mmol) dobijen u primeru pripreme 170 i N-(ciklopropilmetil)-2-jodo-anilin (0.042 g, 0.15 mmol) dobijen u primeru pripreme 73 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.011 g, 21%).[3203] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.054 g, 0.14 mmol) obtained in preparation example 170 and N-(cyclopropylmethyl)-2-iodo-aniline (0.042 g, 0.15 mmol) obtained in preparation example 73 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.011 g, 21%).

[3204] <1>H-NMR (CDCl<3>) δ 7.25 (1H, m), 7.05 (3H, m), 6.74 (1H, t), 6.68 (1H, d), 2.96 (4H, m), 2.57 (2H, t), 1.91 (2H, m), 1.04 (1H, m), 0.49 (2H, m), 0.18 (2H, m).[3204] <1>H-NMR (CDCl<3>) δ 7.25 (1H, m), 7.05 (3H, m), 6.74 (1H, t), 6.68 (1H, d), 2.96 (4H, m), 2.57 (2H, t), 1.91 (2H, m), 1.04 (1H, m), 0.49 (2H, m), 0.18 (2H, m).

[3206] Primer 163: 4-[2-fluoro-4-(2-izopropilsulfanil-piridin-3-il)-fenil sulfanil]-buterna kiselina[3206] Example 163: 4-[2-fluoro-4-(2-isopropylsulfanyl-pyridin-3-yl)-phenyl sulfanyl]-butyric acid

[3207][3207]

[3209] [3209]

[3212] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 180 i 3-jodo-2-izopropilsulfanil-piridin (0.057 g, 0.2 mmol) dobijen u primeru pripreme 226 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.023 g, 46%).[3212] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in preparation example 180 and 3-iodo-2-isopropylsulfanyl-pyridine (0.057 g, 0.2 mmol) obtained in preparation example 226 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.023 g, 46%).

[3213] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.44-7.35 (2H, m), 7.15 (2H, m), 7.05 (1H, m), 4.07 (1H, m), 3.01 (2H, t), 2.57 (2H, t), 1.99 (2H, m), 1.36 (6H, d).[3213] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.44-7.35 (2H, m), 7.15 (2H, m), 7.05 (1H, m), 4.07 (1H, m), 3.01 (2H, t), 2.57 (2H, t), 1.99 (2H, m), 1.36 (6H, d).

[3215] Primer 164: 4-[4-(2-ciklopentilsulfanil-piridin-3-il)-2-fluoro-fenil sulfanil]-buterna kiselina[3215] Example 164: 4-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2-fluoro-phenyl sulfanyl]-butyric acid

[3216][3216]

[3218] [3218]

[3221] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.04 g, 0.11 mmol) dobijen u primeru pripreme 180 i 2-ciklopentilsulfanil-3-jodo-piridin (0.05 g, 0.16 mmol) dobijen u primeru pripreme 39 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.014 g, 33%).[3221] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.04 g, 0.11 mmol) obtained in preparation example 180 and 2-cyclopentylsulfanyl-3-iodo-pyridine (0.05 g, 0.16 mmol) obtained in preparation example 39 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.014 g, 33%).

[3222] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.43-7.35 (2H, m), 7.17 (2H, m), 7.05 (1H, m), 4.09 (1H, m), 3.01 (2H, t), 2.57 (2H, t), 2.18 (2H, m), 1.99 (2H, m), 1.73-1.53 (6H, m).[3222] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.43-7.35 (2H, m), 7.17 (2H, m), 7.05 (1H, m), 4.09 (1H, m), 3.01 (2H, t), 2.57 (2H, t), 2.18 (2H, m), 1.99 (2H, m), 1.73-1.53 (6H, m).

[3223] Primer 165: 4-(3,5-difluoro-2'-izopropilamino-bifenil-4-ilsulfanil)-buterna kiselina[3223] Example 165: 4-(3,5-difluoro-2'-isopropylamino-biphenyl-4-ylsulfanyl)-butyric acid

[3224][3224]

[3226] [3226]

[3229] Etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.13 mmol) dobijen u primeru pripreme 170 i 2-jodo-N-izopropil-anilin (0.05 g, 0.14 mmol) dobijen u primeru pripreme 74 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.033 g, 70%).[3229] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.13 mmol) obtained in Preparation Example 170 and 2-iodo-N-isopropyl-aniline (0.05 g, 0.14 mmol) obtained in Preparation Example 74 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.033 g, 70%).

[3230] <1>H-NMR (CDCl<3>) δ 7.24 (1H, m), 7.02 (3H, m), 6.72 (2H, m), 3.64 (1H, m), 2.98 (2H, t), 2.58 (2H, t), 1.93 (2H, m), 1.17 (6H, d).[3230] <1>H-NMR (CDCl<3>) δ 7.24 (1H, m), 7.02 (3H, m), 6.72 (2H, m), 3.64 (1H, m), 2.98 (2H, t), 2.58 (2H, t), 1.93 (2H, m), 1.17 (6H, d).

[3232] Primer 166: 4-(3,5-difluoro-2'-propilamino-bifenil-4-ilsulfanil)-buterna kiselina[3232] Example 166: 4-(3,5-difluoro-2'-propylamino-biphenyl-4-ylsulfanyl)-butyric acid

[3233][3233]

[3235] [3235]

[3238] Etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.13 mmol) dobijen u primeru pripreme 170 i 2-jodo-N-propil-anilin (0.05 g, 0.14 mmol) dobijen u primeru pripreme 72 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.023 g, 48%).[3238] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.13 mmol) obtained in Preparation Example 170 and 2-iodo-N-propyl-aniline (0.05 g, 0.14 mmol) obtained in Preparation Example 72 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.023 g, 48%).

[3239] <1>H-NMR (CDCl<3>) δ 7.25 (1H, m), 7.04 (3H, m), 6.73 (2H, m), 3.07 (2H, t), 2.97 (2H, t), 2.58 (2H, t), 1.91 (2H, m), 1.57 (2H, m), 0.94 (3H, t).[3239] <1>H-NMR (CDCl<3>) δ 7.25 (1H, m), 7.04 (3H, m), 6.73 (2H, m), 3.07 (2H, t), 2.97 (2H, t), 2.58 (2H, t), 1.91 (2H, m), 1.57 (2H, m), 0.94 (3H, t).

[3241] Primer 167: 4-[4-(2-ciklopropilmetoksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina [1252][3241] Example 167: 4-[4-(2-cyclopropylmethoxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid [1252]

[3243] [3243]

[3246] Etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.13 mmol) dobijen u primeru pripreme 170 i 2-ciklopropilmetoksi-3-jodo-piridin (0.07 g, 0.26 mmol) dobijen u primeru pripreme 40 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.025 g, 51%).[3246] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.13 mmol) obtained in Preparation Example 170 and 2-cyclopropylmethoxy-3-iodo-pyridine (0.07 g, 0.26 mmol) obtained in Preparation Example 170 40 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.025 g, 51%).

[3247] <1>H-NMR (CDCl<3>) δ 8.15 (1H, m), 7.62 (1H, m), 7.24 (2H, d), 6.96 (1H, m), 4.23 (2H, d), 2.97 (2H, t), 2.56 (2H, t), 1.90 (2H, m), 1.29 (1H, m), 0.59 (2H, m), 0.34 (2H, m).[3247] <1>H-NMR (CDCl<3>) δ 8.15 (1H, m), 7.62 (1H, m), 7.24 (2H, d), 6.96 (1H, m), 4.23 (2H, d), 2.97 (2H, t), 2.56 (2H, t), 1.90 (2H, m), 1.29 (1H, m), 0.59 (2H, m), 0.34 (2H, m).

[3249] Primer 168: 4-[2,6-difluoro-4-(2-propilsulfanil-piridin-3il)-fenil sulfanil]-buterna kiselina[3249] Example 168: 4-[2,6-difluoro-4-(2-propylsulfanyl-pyridin-3yl)-phenyl sulfanyl]-butyric acid

[3250][3250]

[3252] [3252]

[3255] Etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.13 mmol) dobijen u primeru pripreme 170 i 3-jodo-2-propilsulfanil-piridin (0.07 g, 0.26 mmol) dobijen u primeru pripreme 203 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.03 g, 61%).[3255] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.13 mmol) obtained in Preparation Example 170 and 3-iodo-2-propylsulfanyl-pyridine (0.07 g, 0.26 mmol) obtained in Preparation Example 170 203 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.03 g, 61%).

[3256] <1>H-NMR (CDCl<3>) δ 8.45 (1H, m), 7.36 (1H, m), 7.07-7.01 (3H, m), 3.15 (2H, t), 2.99 (2H, t), 2.58 (2H, t), 1.92 (2H, m), 1.71 (2H, m), 1.02 (3H, t).[3256] <1>H-NMR (CDCl<3>) δ 8.45 (1H, m), 7.36 (1H, m), 7.07-7.01 (3H, m), 3.15 (2H, t), 2.99 (2H, t), 2.58 (2H, t), 1.92 (2H, m), 1.71 (2H, m), 1.02 (3H, t).

[3258] Primer 169: 4-[4-(6-ciklobutilsulfanil-piridin-2-il)-2-fluoro-fenil sulfanil]-buterna kiselina[3258] Example 169: 4-[4-(6-cyclobutylsulfanyl-pyridin-2-yl)-2-fluoro-phenyl sulfanyl]-butyric acid

[3259][3259]

[3261] [3261]

[3264] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.04 g, 0.11 mmol) dobijen u primeru pripreme 180 i 2-hloro-6-ciklobutilsulfanil-piridin (0.04 g, 0.22 mmol) dobijen u primeru pripreme 19 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.009 g, 21%).[3264] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.04 g, 0.11 mmol) obtained in Preparation Example 180 and 2-chloro-6-cyclobutylsulfanyl-pyridine (0.04 g, 0.22 mmol) obtained in Preparation Example 19 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.009 g, 21%).

[3265] <1>H-NMR (CDCl<3>) δ 7.74 (2H, m), 7.51 (1H, t), 7.43 (1H, t), 7.36 (1H, d), 7.03 (1H, d), 4.41 (1H, m), 3.02 (2H, t), 2.61-2.53 (4H, m), 2.21-2.07 (4H, m), 1.99 (2H, m).[3265] <1>H-NMR (CDCl<3>) δ 7.74 (2H, m), 7.51 (1H, t), 7.43 (1H, t), 7.36 (1H, d), 7.03 (1H, d), 4.41 (1H, m), 3.02 (2H, t), 2.61-2.53 (4H, m), 2.21-2.07 (4H, m), 1.99 (2H, m).

[3267] Primer 170: 4-[4-(2-ciklopentilamino-piridin-3-il)-2-fluoro-fenil sulfanil]-buterna kiselina[3267] Example 170: 4-[4-(2-cyclopentylamino-pyridin-3-yl)-2-fluoro-phenyl sulfanyl]-butyric acid

[3268][3268]

[3270] [3270]

[3271] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 180 i N-ciklopentil-3-jodo-piridin-2-amin (0.06 g, 0.2 mmol) dobijen u primeru pripreme 64 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.016 g, 32%).[3271] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 180 and N-cyclopentyl-3-iodo-pyridin-2-amine (0.06 g, 0.2 mmol) obtained in Preparation Example 64 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.016 g, 32%).

[3272] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.44 (1H, t), 7.21 (1H, m), 7.12 (2H, m), 6.61 (1H, m), 4.32 (1H, m), 3.02 (2H, t), 2.56 (2H, t), 2.09-1.97 (4H, m), 1.61 (4H, m), 1.33 (2H, m).[3272] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.44 (1H, t), 7.21 (1H, m), 7.12 (2H, m), 6.61 (1H, m), 4.32 (1H, m), 3.02 (2H, t), 2.56 (2H, t), 2.09-1.97 (4H, m), 1.61 (4H, m), 1.33 (2H, m).

[3274] Primer 171: 4-[2-fluoro-4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-buterna kiselina[3274] Example 171: 4-[2-fluoro-4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-butyric acid

[3275][3275]

[3277] [3277]

[3280] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 180 i 3-jodo-2-izopropoksi-piridin (0.053 g, 0.2 mmol) dobijen u primeru pripreme 37 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.019 g, 40%).[3280] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 180 and 3-iodo-2-isopropoxy-pyridine (0.053 g, 0.2 mmol) obtained in Preparation Example 37 were used. to react in the same manner as in steps A and B of Example 1 to give the title compound (0.019 g, 40%).

[3281] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.58 (1H, m), 7.39-7.30 (3H, m), 6.92 (1H, m), 5.40 (1H, m), 3.00 (2H, t), 2.56 (2H, t), 1.98 (2H, m), 1.35 (6H, d).[3281] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.58 (1H, m), 7.39-7.30 (3H, m), 6.92 (1H, m), 5.40 (1H, m), 3.00 (2H, t), 2.56 (2H, t), 1.98 (2H, m), 1.35 (6H, d).

[3283] Primer 172: 4-[4-(2-ciklobutoksi-piridin-3-il)-2-fluoro-fenilsulfanil]-buterna kiselina[3283] Example 172: 4-[4-(2-cyclobutoxy-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric acid

[3284][3284]

[3286] [3286]

[3289] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 180 i 2-ciklobutoksi-3-jodo-piridin (0.056 g, 0.2 mmol) dobijen u primeru pripreme 200 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.015 g, 30%).[3289] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 180 and 2-cyclobutoxy-3-iodo-pyridine (0.056 g, 0.2 mmol) obtained in Preparation Example 200 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.015 g, 30%).

[3290] <1>H-NMR (CDCl<3>) δ 8.11 (1H, m), 7.58 (1H, m), 7.40-7.32 (3H, m), 6.93 (1H, m), 5.25 (1H, m), 3.01 (2H, t), 2.57-2.42 (4H, m), 2.11 (2H, m), 1.97 (2H, m), 1.82 (1H, m), 1.67 (1H, m).[3290] <1>H-NMR (CDCl<3>) δ 8.11 (1H, m), 7.58 (1H, m), 7.40-7.32 (3H, m), 6.93 (1H, m), 5.25 (1H, m), 3.01 (2H, t), 2.57-2.42 (4H, m), 2.11 (2H, m), 1.97 (2H, m), 1.82 (1H, m), 1.67 (1H, m).

[3291] Primer 173: 4-[2-fluoro-4-(2-pirolidin-1-il-piridin-3-il)-fenilsulfanil]-buterna kiselina[3291] Example 173: 4-[2-fluoro-4-(2-pyrrolidin-1-yl-pyridin-3-yl)-phenylsulfanyl]-butyric acid

[3292][3292]

[3294] [3294]

[3297] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 180 i 3-jodo-2-pirolidin-1-il-piridin (0.056 g, 0.2 mmol) dobijen u primeru pripreme 204 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.03 g, 61%).[3297] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 180 and 3-iodo-2-pyrrolidin-1-yl-pyridine (0.056 g, 0.2 mmol) obtained in Preparation Example 180 204 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.03 g, 61%).

[3298] <1>H-NMR (CDCl<3>) δ 8.20 (1H, m), 7.40-7.36 (2H, m), 7.10-7.05 (2H, m), 6.71 (1H, m), 3.16 (4H, m), 3.01 (2H, t), 2.56 (2H, t), 1.97 (2H, m), 1.80 (4H, m).[3298] <1>H-NMR (CDCl<3>) δ 8.20 (1H, m), 7.40-7.36 (2H, m), 7.10-7.05 (2H, m), 6.71 (1H, m), 3.16 (4H, m), 3.01 (2H, t), 2.56 (2H, t), 1.97 (2H, m), 1.80 (4H, m).

[3300] Primer 174: 4-[2-fluoro-4-(2-izopropilamino-piridin-3-il)-fenil sulfanil]-buterna kiselina[3300] Example 174: 4-[2-fluoro-4-(2-isopropylamino-pyridin-3-yl)-phenyl sulfanyl]-butyric acid

[3301][3301]

[3303] [3303]

[3306] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 180 i 3-jodo-N-izopropil-piridin-2-amin (0.053 g, 0.2 mmol) dobijen u primeru pripreme 66 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.029 g, 61%).[3306] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in preparation example 180 and 3-iodo-N-isopropyl-pyridin-2-amine (0.053 g, 0.2 mmol) obtained in preparation example 66 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.029 g, 61%).

[3307] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.46 (1H, t), 7.24 (1H, m), 7.15-7.10 (2H, m), 6.62 (1H, m), 4.25 (1H, m), 3.04 (2H, t), 2.57 (2H, t), 2.00 (2H, m), 1.19 (6H, d).[3307] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.46 (1H, t), 7.24 (1H, m), 7.15-7.10 (2H, m), 6.62 (1H, m), 4.25 (1H, m), 3.04 (2H, t), 2.57 (2H, t), 2.00 (2H, m), 1.19 (6H, d).

[3309] Primer 175: 4-(2'-ciklopentilamino-3,5'-difluoro-bifenil-4-ilsulfanil)-buterna kiselina[3309] Example 175: 4-(2'-cyclopentylamino-3,5'-difluoro-biphenyl-4-ylsulfanyl)-butyric acid

[3310][3310]

[3312] [3312]

[3315] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 180 i N-ciklopentil-f-fluoro-2-jodo-anilin (0.046 g, 0.15 mmol) dobijen u primeru pripreme 82 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.02 g, 39%).[3315] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 180 and N-cyclopentyl-f-fluoro-2-iodo-aniline (0.046 g, 0.15 mmol) obtained in Preparation Example 180 82 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.02 g, 39%).

[3316] <1>H-NMR (CDCl<3>) δ 7.43 (1H, t), 7.13 (2H, m), 6.92 (1H, m), 6.78 (1H, m), 6.62 (1H, m), 3.71 (1H, m), 3.01 (2H, t), 2.55 (2H, t), 1.99-1.91 (4H, m), 1.61 (4H, m), 1.36 (2H, m).[3316] <1>H-NMR (CDCl<3>) δ 7.43 (1H, t), 7.13 (2H, m), 6.92 (1H, m), 6.78 (1H, m), 6.62 (1H, m), 3.71 (1H, m), 3.01 (2H, t), 2.55 (2H, t), 1.99-1.91 (4H, m), 1.61 (4H, m), 1.36 (2H, m).

[3318] Primer 176: 4-(2'-ciklopentilamino-5'-fluoro-bifenil-4-ilsulfanil)-buterna kiselina[3318] Example 176: 4-(2'-cyclopentylamino-5'-fluoro-biphenyl-4-ylsulfanyl)-butyric acid

[3319][3319]

[3321] [3321]

[3324] Etil estar 4-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 159 i N-ciklopentil-f-fluoro-2-jodo-anilin (0.048 g, 0.16 mmol) dobijen u primeru pripreme 82 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.028 g, 52%).[3324] 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 159 and N-cyclopentyl-f-fluoro-2-iodo-aniline (0.048 g, 0.16 mmol) obtained in Preparation Example 82 were used. to react in the same manner as in steps A and B of Example 1 to give the title compound (0.028 g, 52%).

[3325] <1>H-NMR (CDCl<3>) δ 7.39 (2H, d), 7.29 (2H, d), 6.91 (1H, m), 6.79 (1H, m), 6.62 (1H, m), 3.71 (1H, m), 3.03 (2H, t), 2.55 (2H, t), 2.02-1.93 (4H, m), 1.59 (4H, m), 1.36 (2H, m).[3325] <1>H-NMR (CDCl<3>) δ 7.39 (2H, d), 7.29 (2H, d), 6.91 (1H, m), 6.79 (1H, m), 6.62 (1H, m), 3.71 (1H, m), 3.03 (2H, t), 2.55 (2H, t), 2.02-1.93 (4H, m), 1.59 (4H, m), 1.36 (2H, m).

[3327] Primer 177: 4-(2'-ciklopentiloksi-5'-metil-bifenil-4-ilsulfanil)-buterna kiselina[3327] Example 177: 4-(2'-cyclopentyloxy-5'-methyl-biphenyl-4-ylsulfanyl)-butyric acid

[3328][3328]

[3330] [3330]

[3333] Etil estar 4-(2'-ciklopentiloksi-5'-metil-bifenil-4-ilsulfanil)-buterne kiseline (0.02 g, 0.05 mmol) dobijen u primeru pripreme 187 je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.01 g, 55%).[3333] 4-(2'-Cyclopentyloxy-5'-methyl-biphenyl-4-ylsulfanyl)-butyric acid ethyl ester (0.02 g, 0.05 mmol) obtained in Preparative Example 187 was used to react in the same manner as in Step B of Example 1 to give the title compound (0.01 g, 55%).

[3334] <1>H-NMR (CDCl<3>) δ 7.45 (2H, d), 7.34 (2H, d), 7.10 (1H, s), 7.04 (1H, m), 6.86 (1H, d), 4.67 (1H, m), 3.00 (2H, t), 2.53 (2H, t), 2.31 (3H, s), 1.98 (2H, m), 1.77 (4H, m), 1.64-1.53 (4H, m).[3334] <1>H-NMR (CDCl<3>) δ 7.45 (2H, d), 7.34 (2H, d), 7.10 (1H, s), 7.04 (1H, m), 6.86 (1H, d), 4.67 (1H, m), 3.00 (2H, t), 2.53 (2H, t), 2.31 (3H, s), 1.98 (2H, m), 1.77 (4H, m), 1.64-1.53 (4H, m).

[3335] Primer 178: 4-(2'-ciklopentiloksi-4'-metoksi-bifenil-4-ilsulfanil)-buterna kiselina[3335] Example 178: 4-(2'-cyclopentyloxy-4'-methoxy-biphenyl-4-ylsulfanyl)-butyric acid

[3336][3336]

[3338] [3338]

[3341] Etil estar 4-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.025 g, 0.07 mmol) dobijen u primeru pripreme 159 i 1-bromo-2-ciklopentiloksi-4-metoksi-benzen (0.02 g, 0.07 mmol) dobijen u primeru pripreme 128 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.002 g, 7%).[3341] 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.025 g, 0.07 mmol) obtained in Preparation Example 159 and 1-bromo-2-cyclopentyloxy-4-methoxy-benzene (0.02 g, 0.07 mmol) obtained in Preparation Example 128 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.002 g, 7%).

[3342] <1>H-NMR (CDCl<3>) δ 7.45 (2H, d), 7.34 (2H, d), 7.10 (1H, s), 7.04 (1H, d), 6.86 (1H, d), 4.67 (1H, m), 3.00 (2H, t), 2.53 (2H, t), 2.31 (3H, s), 1.98 (2H, m), 1.77 (4H, m), 1.64-1.53 (4H, m).[3342] <1>H-NMR (CDCl<3>) δ 7.45 (2H, d), 7.34 (2H, d), 7.10 (1H, s), 7.04 (1H, d), 6.86 (1H, d), 4.67 (1H, m), 3.00 (2H, t), 2.53 (2H, t), 2.31 (3H, s), 1.98 (2H, m), 1.77 (4H, m), 1.64-1.53 (4H, m).

[3344] Primer 179: 4-(2'-ciklopentiloksi-5'-fluoro-bifenil-4-ilsulfanil)-buterna kiselina[3344] Example 179: 4-(2'-cyclopentyloxy-5'-fluoro-biphenyl-4-ylsulfanyl)-butyric acid

[3345][3345]

[3347] [3347]

[3350] Etil estar 4-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 159 i 2-bromo-1-ciklopentiloksi-f-fluoro-benzen (0.04 g, 0.16 mmol) dobijen u primeru pripreme 129 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.003 g, 5%).[3350] 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 159 and 2-bromo-1-cyclopentyloxy-f-fluoro-benzene (0.04 g, 0.16 mmol) obtained in Preparation Example 129 were used. to react in the same manner as in steps A and B of Example 1 to give the title compound (0.003 g, 5%).

[3351] <1>H-NMR (CDCl<3>) δ 7.43 (2H, d), 7.32 (2H, d), 7.02 (1H, m), 6.95 (1H, m), 6.88 (1H, m), 4.63 (1H, m), 3.01 (2H, t), 2.53 (2H, t), 1.99 (2H, m), 1.75 (4H, m), 1.63-1.52 (4H, m).[3351] <1>H-NMR (CDCl<3>) δ 7.43 (2H, d), 7.32 (2H, d), 7.02 (1H, m), 6.95 (1H, m), 6.88 (1H, m), 4.63 (1H, m), 3.01 (2H, t), 2.53 (2H, t), 1.99 (2H, m), 1.75 (4H, m), 1.63-1.52 (4H, m).

[3353] Primer 180: 4-(2'-ciklopentiloksi-3,5'-difluoro-bifenil-4-ilsulfanil)-buterna kiselina[3353] Example 180: 4-(2'-cyclopentyloxy-3,5'-difluoro-biphenyl-4-ylsulfanyl)-butyric acid

[3354][3354]

[3356] [3356]

[3358] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.1 g, 0.27 mmol) dobijen u primeru pripreme 180 i 2-bromo-1-ciklopentiloksi-f-fluoro-benzen (0.1 g, 0.4 mmol) dobijen u primeru pripreme 129 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.047 g, 44%).[3358] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.1 g, 0.27 mmol) obtained in Preparation Example 180 and 2-bromo-1-cyclopentyloxy-f-fluoro-benzene (0.1 g, 0.4 mmol) obtained in Preparation Example 129 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.047 g, 44%).

[3359] <1>H-NMR (CDCl<3>) δ 7.38 (1H, t), 7.27-7.24 (2H, m), 7.03 (1H, m), 6.97 (1H, m), 6.89 (1H, m), 4.66 (1H, m), 3.01 (2H, t), 2.55 (2H, t), 1.98 (2H, m), 1.79 (4H, m), 1.70-1.47 (4H, m).[3359] <1>H-NMR (CDCl<3>) δ 7.38 (1H, t), 7.27-7.24 (2H, m), 7.03 (1H, m), 6.97 (1H, m), 6.89 (1H, m), 4.66 (1H, m), 3.01 (2H, t), 2.55 (2H, t), 1.98 (2H, m), 1.79 (4H, m), 1.70-1.47 (4H, m).

[3361] Primer 181: 4- [4-(2-ciklopentiloksi-5-metil-piridin-3-il)-fenilsulfanil] -buterna kiselina[3361] Example 181: 4-[4-(2-cyclopentyloxy-5-methyl-pyridin-3-yl)-phenylsulfanyl]-butyric acid

[3362][3362]

[3364] [3364]

[3367] Etil estar 4-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.1 g, 0.28 mmol) dobijen u primeru pripreme 159 i 3-bromo-2-ciklopentiloksi-5-metil-piridin (0.11 g, 0.43 mmol) dobijen u primeru pripreme 131 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.03 g, 28%).[3367] 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.1 g, 0.28 mmol) obtained in Preparation Example 159 and 3-bromo-2-cyclopentyloxy-5-methyl-pyridine (0.11 g, 0.43 mmol) obtained in Preparation Example 131 were used. to react in the same manner as in steps A and B of Example 1 to give the title compound (0.03 g, 28%).

[3368] <1>H-NMR (CDCl<3>) δ 7.91 (1H, s), 7.48 (2H, d), 7.40 (1H, s), 7.34 (2H, d), 5.44 (1H, m), 3.01 (2H, t), 2.54 (2H, t), 2.26 (3H, s), 2.01 (2H, m), 1.90 (2H, m), 1.78-1.58 (6H, m).[3368] <1>H-NMR (CDCl<3>) δ 7.91 (1H, s), 7.48 (2H, d), 7.40 (1H, s), 7.34 (2H, d), 5.44 (1H, m), 3.01 (2H, t), 2.54 (2H, t), 2.26 (3H, s), 2.01 (2H, m), 1.90 (2H, m), 1.78-1.58 (6H, m).

[3370] Primer 182: 4-(2'-ciklopentiloksi-3,5,5'-trifluoro-bifenil-4-ilsulfanil)-buterna kiselina[3370] Example 182: 4-(2'-cyclopentyloxy-3,5,5'-trifluoro-biphenyl-4-ylsulfanyl)-butyric acid

[3371][3371]

[3373] [3373]

[3376] Etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.036 g, 0.09 mmol) dobijen u primeru pripreme 170 i 2-bromo-1-ciklopentiloksi-f-fluorobenzen (0.026 g, 0.1 mmol) dobijen u primeru pripreme 129 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.002 g, 4%).[3376] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.036 g, 0.09 mmol) obtained in Preparation Example 170 and 2-bromo-1-cyclopentyloxy-f-fluorobenzene (0.026 g, 0.1 mmol) obtained in Preparation Example 170 129 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.002 g, 4%).

[3377] <1>H-NMR (CDCl<3>) δ 7.11 (2H, d), 7.02 (2H, m), 6.89 (1H, m), 4.68 (1H, m), 2.95 (2H, t), 2.53 (2H, m), 1.89-1.79 (6H, m), 1.66-1.58 (4H, m).[3377] <1>H-NMR (CDCl<3>) δ 7.11 (2H, d), 7.02 (2H, m), 6.89 (1H, m), 4.68 (1H, m), 2.95 (2H, t), 2.53 (2H, m), 1.89-1.79 (6H, m), 1.66-1.58 (4H, m).

[3378] Primer 183: 4-(2'-ciklopentiloksi-3-fluoro-4'-metoksi-bifenil-4-ilsulfanil)-buterna kiselina[3378] Example 183: 4-(2'-cyclopentyloxy-3-fluoro-4'-methoxy-biphenyl-4-ylsulfanyl)-butyric acid

[3379][3379]

[3381] [3381]

[3384] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.13 mmol) dobijen u primeru pripreme 180 i 1-bromo-2-ciklopentiloksi-4-metoksi-benzen (0.04 g, 0.15 mmol) dobijen u primeru pripreme 128 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.005 g, 9%).[3384] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.13 mmol) obtained in preparation example 180 and 1-bromo-2-cyclopentyloxy-4-methoxy-benzene (0.04 g, 0.15 mmol) obtained in preparation example 128 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.005 g, 9%).

[3385] <1>H-NMR (CDCl<3>) δ 7.38 (1H, t), 7.28-7.21 (4H, m), 6.53 (1H, m), 4.74 (1H, m), 3.83 (3H, s), 2.98 (2H, t), 2.55 (2H, t), 1.99 (2H, m), 1.84 (4H, m), 1.71-1.58 (4H, m).[3385] <1>H-NMR (CDCl<3>) δ 7.38 (1H, t), 7.28-7.21 (4H, m), 6.53 (1H, m), 4.74 (1H, m), 3.83 (3H, s), 2.98 (2H, t), 2.55 (2H, t), 1.99 (2H, m), 1.84 (4H, m), 1.71-1.58 (4H, m).

[3387] Primer 184: 4-(2'-ciklopentiloksi-3,5-difluoro-4'-metoksi-bifenil-4-ilsulfanil)-buterna kiselina [1303][3387] Example 184: 4-(2'-cyclopentyloxy-3,5-difluoro-4'-methoxy-biphenyl-4-ylsulfanyl)-butyric acid [1303]

[3389] [3389]

[3392] Etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.13 mmol) dobijen u primeru pripreme 170 i 1-bromo-2-ciklopentiloksi-4-metoksibenzen (0.04 g, 0.14 mmol) dobijen u primeru pripreme 128 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.004 g, 7%).[3392] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.13 mmol) obtained in Preparation Example 170 and 1-bromo-2-cyclopentyloxy-4-methoxybenzene (0.04 g, 0.14 mmol) obtained in Preparation Example 170 128 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.004 g, 7%).

[3393] <1>H-NMR (CDCl<3>) δ 7.22 (1H, m), 7.10 (2H, d), 6.55 (2H, m), 4.76 (1H, m), 3.84 (3H, s), 2.94 (2H, t), 2.56 (2H, t), 1.91-1.86 (6H, m), 1.71 (2H, m), 1.62 (2H, m).[3393] <1>H-NMR (CDCl<3>) δ 7.22 (1H, m), 7.10 (2H, d), 6.55 (2H, m), 4.76 (1H, m), 3.84 (3H, s), 2.94 (2H, t), 2.56 (2H, t), 1.91-1.86 (6H, m), 1.71 (2H, m), 1.62 (2H, m).

[3395] Primer 185: 4-(3-fluoro-2'-izopropoksi-4'-metoksi-bifenil-4-ilsulfanil)-buterna kiselina[3395] Example 185: 4-(3-fluoro-2'-isopropoxy-4'-methoxy-biphenyl-4-ylsulfanyl)-butyric acid

[3396][3396]

[3398] [3398]

[3401] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.13 mmol) dobijen u primeru pripreme 180 i 1-bromo-2-izopropoksi-4-metoksi-benzen (0.04 g, 0.15 mmol) dobijen u primeru pripreme 132 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.007 g, 13%).[3401] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.13 mmol) obtained in preparation example 180 and 1-bromo-2-isopropoxy-4-methoxy-benzene (0.04 g, 0.15 mmol) obtained in preparation example 180 132 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.007 g, 13%).

[3402] <1>H-NMR (CDCl<3>) δ 7.37 (1H, t), 7.30-7.22 (3H, m), 6.56 (2H, m), 4.47 (1H, m), 3.84 (3H, s), 2.99 (2H, t), 2.56 (2H, t), 1.96 (2H, m), 1.29 (6H, d).[3402] <1>H-NMR (CDCl<3>) δ 7.37 (1H, t), 7.30-7.22 (3H, m), 6.56 (2H, m), 4.47 (1H, m), 3.84 (3H, s), 2.99 (2H, t), 2.56 (2H, t), 1.96 (2H, m), 1.29 (6H, d).

[3404] Primer 186: 4-[4-(2-ciklopentiloksi-5-metil-piridin-3-il)-2-fluoro-fenilsulfanil]-buterna kiselina [1309][3404] Example 186: 4-[4-(2-cyclopentyloxy-5-methyl-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric acid [1309]

[3406] [3406]

[3409] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 180 i 3-bromo-2-ciklopentiloksi-5-metil-piridin (0.05 g, 0.2 mmol) dobijen u primeru pripreme 131 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.018 g, 34%).[3409] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in preparation example 180 and 3-bromo-2-cyclopentyloxy-5-methyl-pyridine (0.05 g, 0.2 mmol) obtained in preparation example 180 131 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.018 g, 34%).

[3410] <1>H-NMR (CDCl<3>) δ 7.96 (1H, s), 7.43 (1H, s), 7.38 (1H, t), 7.31-7.25 (2H, m), 5.47 (1H, m), 3.00 (2H, t), 2.55 (2H, t), 2.27 (3H, s), 1.98-1.93 (4H, m), 1.78-1.61 (6H, m).[3410] <1>H-NMR (CDCl<3>) δ 7.96 (1H, s), 7.43 (1H, s), 7.38 (1H, t), 7.31-7.25 (2H, m), 5.47 (1H, m), 3.00 (2H, t), 2.55 (2H, t), 2.27 (3H, s), 1.98-1.93 (4H, m), 1.78-1.61 (6H, m).

[3412] Primer 187: 4-[2-fluoro-4-(2-izopropoksi-5-metil-piridin-3-il)-fenilsulfanil]-buterna kiselina [1312][3412] Example 187: 4-[2-fluoro-4-(2-isopropoxy-5-methyl-pyridin-3-yl)-phenylsulfanyl]-butyric acid [1312]

[3414] [3414]

[3417] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 180 i 3-bromo-2-izopropoksi-5-metil-piridin (0.05 g, 0.2 mmol) dobijen u primeru pripreme 133 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.017 g, 34%).[3417] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in preparation example 180 and 3-bromo-2-isopropoxy-5-methyl-pyridine (0.05 g, 0.2 mmol) obtained in preparation example 133 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.017 g, 34%).

[3418] <1>H-NMR (CDCl<3>) δ 7.94 (1H, s), 7.43 (1H, s), 7.41 (1H, t), 7.38-7.30 (2H, m), 5.34 (1H, m), 3.00 (2H, t), 2.55 (2H, t), 2.27 (3H, s), 1.97 (2H, m), 1.32 (6H, d).[3418] <1>H-NMR (CDCl<3>) δ 7.94 (1H, s), 7.43 (1H, s), 7.41 (1H, t), 7.38-7.30 (2H, m), 5.34 (1H, m), 3.00 (2H, t), 2.55 (2H, t), 2.27 (3H, s), 1.97 (2H, m), 1.32 (6H, d).

[3419] Primer 188: 4-(3,5'-difluoro-2'-izopropoksi-bifenil-4-ilsulfanil)-buterna kiselina[3419] Example 188: 4-(3,5'-difluoro-2'-isopropoxy-biphenyl-4-ylsulfanyl)-butyric acid

[3420][3420]

[3422] [3422]

[3425] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 180 i 2-bromo-f-fluoro-1-izopropoksi-benzen (0.05 g, 0.2 mmol) dobijen u primeru pripreme 134 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.02 g, 40%).[3425] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 180 and 2-bromo-f-fluoro-1-isopropoxy-benzene (0.05 g, 0.2 mmol) obtained in Preparation Example 134 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.02 g, 40%).

[3426] <1>H-NMR (CDCl<3>) δ 7.39 (1H, t), 7.33-7.27 (2H, m), 7.05-6.90 (3H, m), 4.33 (1H, m), 3.01 (2H, t), 2.56 (2H, t), 1.97 (2H, m), 1.24 (6H, d).[3426] <1>H-NMR (CDCl<3>) δ 7.39 (1H, t), 7.33-7.27 (2H, m), 7.05-6.90 (3H, m), 4.33 (1H, m), 3.01 (2H, t), 2.56 (2H, t), 1.97 (2H, m), 1.24 (6H, d).

[3428] Primer 189: 4-[4-(2-ciklopentiloksi-6-metil-piridin-3-il)-2-fluoro-fenilsulfanil]-buterna kiselina [1318][3428] Example 189: 4-[4-(2-cyclopentyloxy-6-methyl-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric acid [1318]

[3430] [3430]

[3433] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 180 i 3-bromo-2-ciklopentiloksi-6-metil-piridin (0.05 g, 0.2 mmol) dobijen u primeru pripreme 136 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.011 g, 20%).[3433] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in preparation example 180 and 3-bromo-2-cyclopentyloxy-6-methyl-pyridine (0.05 g, 0.2 mmol) obtained in preparation example 180 136 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.011 g, 20%).

[3434] <1>H-NMR (CDCl<3>) δ 7.39 (2H, m), 7.01 (2H, m), 6.55 (1H, d), 5.34 (1H, m), 2.99 (2H, t), 2.54 (2H, t), 2.39 (3H, s), 2.01-1.91 (4H, m), 1.81 (4H, m), 1.62 (2H, m).[3434] <1>H-NMR (CDCl<3>) δ 7.39 (2H, m), 7.01 (2H, m), 6.55 (1H, d), 5.34 (1H, m), 2.99 (2H, t), 2.54 (2H, t), 2.39 (3H, s), 2.01-1.91 (4H, m), 1.81 (4H, m), 1.62 (2H, m).

[3436] Primer 190: 4-(3,3'-difluoro-2'-izopropoksi-5'-metil-bifenil-4-ilsulfanil)-buterna kiselina[3436] Example 190: 4-(3,3'-difluoro-2'-isopropoxy-5'-methyl-biphenyl-4-ylsulfanyl)-butyric acid

[3437][3437]

[3439] [3439]

[3442] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 180 i 1-bromo-3-fluoro-2-izopropoksi-5-metil-benzen (0.05 g, 0.2 mmol) dobijen u primeru pripreme 138 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.022 g, 43%).[3442] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in preparation example 180 and 1-bromo-3-fluoro-2-isopropoxy-5-methyl-benzene (0.05 g, 0.2 mmol) obtained in preparation example 138 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.022 g, 43%).

[3443] <1>H-NMR (CDCl<3>) δ 7.39 (1H, t), 7.31 (2H, m), 6.91 (2H, m), 3.97 (1H, m), 2.99 (2H, t), 2.55 (2H, t), 2.33 (3H, s), 1.94 (2H, m), 1.05 (6H, d).[3443] <1>H-NMR (CDCl<3>) δ 7.39 (1H, t), 7.31 (2H, m), 6.91 (2H, m), 3.97 (1H, m), 2.99 (2H, t), 2.55 (2H, t), 2.33 (3H, s), 1.94 (2H, m), 1.05 (6H, d).

[3445] Primer 191: 4-(3,3' -difluoro-5' -metil-2' -propoksi-bifenil-4-ilsulfanil)-buterna kiselina[3445] Example 191: 4-(3,3'-difluoro-5'-methyl-2'-propoxy-biphenyl-4-ylsulfanyl)-butyric acid

[3446][3446]

[3448] [3448]

[3451] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 180 i 1-bromo-3-fluoro-5-metil-2-propoksi-benzen (0.05 g, 0.2 mmol) dobijen u primeru pripreme 139 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.02 g, 39%).[3451] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in preparation example 180 and 1-bromo-3-fluoro-5-methyl-2-propoxy-benzene (0.05 g, 0.2 mmol) obtained in preparation example 139 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.02 g, 39%).

[3452] <1>H-NMR (CDCl<3>) δ 7.39 (1H, t), 7.26 (2H, m), 6.91 (2H, m), 3.72 (2H, t), 2.99 (2H, t), 2.55 (2H, t), 2.31 (3H, s), 1.94 (2H, m), 1.55 (2H, m), 0.82 (3H, t).[3452] <1>H-NMR (CDCl<3>) δ 7.39 (1H, t), 7.26 (2H, m), 6.91 (2H, m), 3.72 (2H, t), 2.99 (2H, t), 2.55 (2H, t), 2.31 (3H, s), 1.94 (2H, m), 1.55 (2H, m), 0.82 (3H, t).

[3454] Primer 192: 4-(3-fluoro-2',4'-dipropoksi-bifenil-4-ilsulfanil)-buterna kiselina[3454] Example 192: 4-(3-fluoro-2',4'-dipropoxy-biphenyl-4-ylsulfanyl)-butyric acid

[3455][3455]

[3457] [3457]

[3460] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 180 i 1-bromo-2,4-dipropoksi-benzen (0.056 g, 0.2 mmol) dobijen u primeru pripreme 140 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje(0.033 g, 60%).[3460] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 180 and 1-bromo-2,4-dipropoxy-benzene (0.056 g, 0.2 mmol) obtained in Preparation Example 140 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.033 g, 60%).

[3461] <1>H-NMR (CDCl<3>) δ 7.37 (1H, t), 7.28-7.21 (3H, m), 6.53 (2H, m), 3.93 (4H, m), 2.98 (2H, t), 2.55 (2H, t), 1.95 (2H, m), 1.87-1.72 (4H, m), 1.05 (3H, m), 0.98 (3H, m).[3461] <1>H-NMR (CDCl<3>) δ 7.37 (1H, t), 7.28-7.21 (3H, m), 6.53 (2H, m), 3.93 (4H, m), 2.98 (2H, t), 2.55 (2H, t), 1.95 (2H, m), 1.87-1.72 (4H, m), 1.05 (3H, m), 0.98 (3H, m).

[3462] Primer 193: 4-(6'-ciklopentiloksi-3,2'-difluoro-3'-metil-bifenil-4-il sulfanil)-buterna kiselina [1330][3462] Example 193: 4-(6'-cyclopentyloxy-3,2'-difluoro-3'-methyl-biphenyl-4-yl sulfanyl)-butyric acid [1330]

[3464] [3464]

[3467] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 180 i 2-bromo-1-ciklopentiloksi-3-fluoro-4-metil-benzen (0.056 g, 0.2 mmol) dobijen u primeru pripreme 142 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.035 g, 63%).[3467] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in preparation example 180 and 2-bromo-1-cyclopentyloxy-3-fluoro-4-methyl-benzene (0.056 g, 0.2 mmol) obtained in example Preparation 142 was used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.035 g, 63%).

[3468] <1>H-NMR (CDCl<3>) δ 7.41 (1H, t), 7.31-7.26 (2H, m), 6.89-6.83 (2H, m), 4.03 (1H, m), 3.00 (2H, t), 2.56 (2H, t), 2.31 (3H, s), 1.94 (2H, m), 1.57 (4H, m), 1.40 (4H, m).[3468] <1>H-NMR (CDCl<3>) δ 7.41 (1H, t), 7.31-7.26 (2H, m), 6.89-6.83 (2H, m), 4.03 (1H, m), 3.00 (2H, t), 2.56 (2H, t), 2.31 (3H, s), 1.94 (2H, m), 1.57 (4H, m), 1.40 (4H, m).

[3470] Primer 194: 4-(2'-ciklopentiloksi-3,3'-difluoro-bifenil-4-ilsulfanil)-buterna kiselina[3470] Example 194: 4-(2'-cyclopentyloxy-3,3'-difluoro-biphenyl-4-ylsulfanyl)-butyric acid

[3471][3471]

[3473] [3473]

[3476] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 180 i 1-bromo-2-ciklopentiloksi-3-fluoro-benzen (0.053 g, 0.2 mmol) dobijen u primeru pripreme 144 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.01 g, 18%).[3476] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in preparation example 180 and 1-bromo-2-cyclopentyloxy-3-fluoro-benzene (0.053 g, 0.2 mmol) obtained in preparation example 144 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.01 g, 18%).

[3477] <1>H-NMR (CDCl<3>) δ 7.42 (1H, t), 7.30-7.21 (4H, m), 7.01 (1H, t), 4.84 (1H, m), 2.99 (2H, t), 2.55 (2H, t), 1.99-1.83 (8H, m), 1.64 (2H, m).[3477] <1>H-NMR (CDCl<3>) δ 7.42 (1H, t), 7.30-7.21 (4H, m), 7.01 (1H, t), 4.84 (1H, m), 2.99 (2H, t), 2.55 (2H, t), 1.99-1.83 (8H, m), 1.64 (2H, m).

[3479] Primer 195: 4-(2'-ciklopentiloksi-3,3'-difluoro-5'-metil-bifenil-4-ilsulfanil)-buterna kiselina[3479] Example 195: 4-(2'-cyclopentyloxy-3,3'-difluoro-5'-methyl-biphenyl-4-ylsulfanyl)-butyric acid

[3480][3480]

[3482] [3482]

[3485] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 180 i 1-bromo-2-ciklopentiloksi-3-fluoro-5-metil-benzen (0.053 g, 0.2 mmol) dobijen u primeru pripreme 145 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.025 g, 45%).[3485] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 180 and 1-bromo-2-cyclopentyloxy-3-fluoro-5-methyl-benzene (0.053 g, 0.2 mmol) obtained in Example Preparation 145 was used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.025 g, 45%).

[3486] <1>H-NMR (CDCl<3>) δ 7.40 (1H, t), 7.38-7.26 (2H, m), 6.91 (2H, m), 4.46 (1H, m), 2.99 (2H, t), 2.55 (2H, t), 2.32 (3H, s), 1.94 (2H, m), 1.65 (2H, m), 1.47-1.39 (6H, m).[3486] <1>H-NMR (CDCl<3>) δ 7.40 (1H, t), 7.38-7.26 (2H, m), 6.91 (2H, m), 4.46 (1H, m), 2.99 (2H, t), 2.55 (2H, t), 2.32 (3H, s), 1.94 (2H, m), 1.65 (2H, m), 1.47-1.39 (6H, m).

[3488] Primer 196: 5-[4-(2-ciklobutilmetoksi-piridin-3-il)-2,6-difluoro-fenoksi]-valerijanska kiselina [1339][3488] Example 196: 5-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-valeric acid [1339]

[3490] [3490]

[3493] 2-ciklobutilmetoksi-3-jodo-piridin (0.040 g, 0.14 mmol) dobijen u primeru pripreme 61 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.053 g, 0.14 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.029 g, 54 %).[3493] 2-cyclobutylmethoxy-3-iodo-pyridine (0.040 g, 0.14 mmol) obtained in Preparation Example 61 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.053 g, 0.14 mmol) obtained in Preparation Example 2 were used to would react in the same way as in steps A and B of Example 1 to give the title compound (0.029 g, 54 %).

[3494] 1H NMR (CDCl<3>) δ 8.14 (1H, m), 7.59 (1H, m), 7.16 (2H, m), 6.94 (1H, m), 4.33 (2H, d), 4.20 (2H, t), 2.79 (1H, m), 2.48 (2H, t), 2.14 (2H, m), 2.00-1.80 (8H, m)[3494] 1H NMR (CDCl<3>) δ 8.14 (1H, m), 7.59 (1H, m), 7.16 (2H, m), 6.94 (1H, m), 4.33 (2H, d), 4.20 (2H, t), 2.79 (1H, m), 2.48 (2H, t), 2.14 (2H, m), 2.00-1.80 (8H, m)

[3496] Primer 197: 5-[4-(2-ciklopropoksi-piridin-3-il)-2,6-difluoro-fenoksi]-valerijanska kiselina[3496] Example 197: 5-[4-(2-cyclopropoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-valeric acid

[3497][3497]

[3499] [3499]

[3502] 2-ciklopropoksi-3-jodo-piridin (0.040 g, 0.15 mmol) dobijen u primeru pripreme 62 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.059 g, 0.15 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.024 g, 43 %).[3502] 2-cyclopropoxy-3-iodo-pyridine (0.040 g, 0.15 mmol) obtained in Preparation Example 62 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.059 g, 0.15 mmol) obtained in Preparation Example 2 were used to reacted in the same manner as in steps A and B of Example 1 to give the title compound (0.024 g, 43 %).

[3503] 1H NMR (CDCl<3>) δ 8.23 (1H, m), 7.57 (1H, m), 7.07 (2H, m), 7.00 (1H, m), 4.34 (1H, m), 4.18 (2H, t), 2.48 (2H, t), 1.89 (4H, m), 0.82 (2H, m), 0.75 (2H, m)[3503] 1H NMR (CDCl<3>) δ 8.23 (1H, m), 7.57 (1H, m), 7.07 (2H, m), 7.00 (1H, m), 4.34 (1H, m), 4.18 (2H, t), 2.48 (2H, t), 1.89 (4H, m), 0.82 (2H, m), 0.75 (2H, m)

[3504] Primer 198: 4-[4-(2-ciklopentiloksi-5-metil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina [1345][3504] Example 198: 4-[4-(2-cyclopentyloxy-5-methyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid [1345]

[3506] [3506]

[3509] Etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.13 mmol) dobijen u primeru pripreme 170 i 3-bromo-2-ciklopentiloksi-5-metil-piridin (0.05 g, 0.26 mmol) dobijen u primeru pripreme 131 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.02 g, 40%).[3509] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.13 mmol) obtained in Preparation Example 170 and 3-bromo-2-cyclopentyloxy-5-methyl-pyridine (0.05 g, 0.26 mmol) obtained in Example Preparation 131 was used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.02 g, 40%).

[3510] <1>H-NMR (CDCl<3>) δ 7.97 (1H, s), 7.42 (1H, s), 7.16 (2H, d), 5.47 (1H, m), 2.95 (2H, t), 2.55 (2H, t), 2.27 (3H, s), 1.92 (4H, m), 1.88-1.62 (6H, m).[3510] <1>H-NMR (CDCl<3>) δ 7.97 (1H, s), 7.42 (1H, s), 7.16 (2H, d), 5.47 (1H, m), 2.95 (2H, t), 2.55 (2H, t), 2.27 (3H, s), 1.92 (4H, m), 1.88-1.62 (6H, m).

[3512] Primer 199: 4-[4-(2-ciklopentiloksi-piridin-3-il)-fenilsulfanil]-valerijanska kiselina[3512] Example 199: 4-[4-(2-cyclopentyloxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid

[3513][3513]

[3515] [3515]

[3518] Etil estar 4-[4-(2-ciklopentiloksi-piridin-3-il)-fenilsulfanil]-valerijanske kiseline (0.01 g, 0.02 mmol) dobijen u primeru pripreme 191 je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.005 g, 48%).[3518] 4-[4-(2-cyclopentyloxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid ethyl ester (0.01 g, 0.02 mmol) obtained in Preparative Example 191 was used to react in the same manner as in Step B of Example 1 to give the title compound (0.005 g, 48%).

[3519] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.57 (1H, m), 7.49 (2H, d), 7.41 (2H, d), 6.90 (1H, m), 5.49 (1H, m), 3.29 (1H, m), 2.59 (2H, t), 1.93-1.91 (4H, m), 1.82-1.59 (6H, m), 1.34 (3H, d).[3519] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.57 (1H, m), 7.49 (2H, d), 7.41 (2H, d), 6.90 (1H, m), 5.49 (1H, m), 3.29 (1H, m), 2.59 (2H, t), 1.93-1.91 (4H, m), 1.82-1.59 (6H, m), 1.34 (3H, d).

[3521] Primer 200: 4-[4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-valerijanska kiselina[3521] Example 200: 4-[4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid

[3522][3522]

[3524] [3524]

[3527] Etil estar (E)-4-[4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-pent-2-pelargonske kiseline (0.025 g, 0.07 mmol) dobijen u primeru pripreme 193 je korišćen da bi reagovao sekvencijalno na isti način kao u primeru pripreme 191 i fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.005 g, 20%).[3527] (E)-4-[4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-pent-2-pelargonic acid ethyl ester (0.025 g, 0.07 mmol) obtained in Preparative Example 193 was used to react sequentially in the same manner as in Preparative Example 191 and Phase B of Example 1 to give the title compound (0.005 g, 20%).

[3528] <1>H-NMR (CDCl<3>) δ 8.11 (1H, m), 7.57 (1H, m), 7.51 (2H, d), 7.42 (2H, d), 6.90 (1H, m), 5.38 (1H, m), 3.29 (1H, m), 2.60 (2H, t), 1.93 (2H, m), 1.34 (9H, m).[3528] <1>H-NMR (CDCl<3>) δ 8.11 (1H, m), 7.57 (1H, m), 7.51 (2H, d), 7.42 (2H, d), 6.90 (1H, m), 5.38 (1H, m), 3.29 (1H, m), 2.60 (2H, t), 1.93 (2H, m), 1.34 (9H, m).

[3530] Primer 201: 4-[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenil sulfanil]-valerijanska kiselina [1354][3530] Example 201: 4-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenyl sulfanyl]-valeric acid [1354]

[3532] [3532]

[3535] Etil estar (E)-4-[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-pent-2-pelargonske kiseline (0.04 g, 0.09 mmol) dobijen u primeru pripreme 197 je korišćen da bi reagovao sekvencijalno na isti način kao u primeru pripreme 191 i fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.01 g, 26%).[3535] (E)-4-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-pent-2-pelargonic acid ethyl ester (0.04 g, 0.09 mmol) obtained in Preparative Example 197 was used to react sequentially in the same manner as in Preparative Example 191 and Phase B of Example 1 to give the title compound (0.01 g, 26%).

[3536] <1>H-NMR (CDCl<3>) δ 8.17 (1H, m), 7.61 (1H, m), 7.19 (2H, d), 6.93 (1H, m), 5.51 (1H, m), 3.31 (1H, m), 2.62 (2H, t), 1.94 (2H, m), 1.86-1.73 (6H, m), 1.63 (2H, m), 1.30 (3H, d).[3536] <1>H-NMR (CDCl<3>) δ 8.17 (1H, m), 7.61 (1H, m), 7.19 (2H, d), 6.93 (1H, m), 5.51 (1H, m), 3.31 (1H, m), 2.62 (2H, t), 1.94 (2H, m), 1.86-1.73 (6H, m), 1.63 (2H, m), 1.30 (3H, d).

[3538] Primer 202: 4-[4-(2-ciklopentilsulfanil-piridin-3-il)-2,6-difluoro-fenil sulfanil]-valerijanska kiselina [1357][3538] Example 202: 4-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenyl sulfanyl]-valeric acid [1357]

[3540] [3540]

[3543] Etil estar (E)-4-[4-(2-ciklopentilsulfanil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-pent-2-pelargonske kiseline (0.04 g, 0.09 mmol) dobijen u primeru pripreme 199 je korišćen da bi reagovao sekvencijalno na isti način kao u primeru pripreme 191 i fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.005 g, 12%).[3543] (E)-4-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-pent-2-pelargonic acid ethyl ester (0.04 g, 0.09 mmol) obtained in Preparative Example 199 was used to react sequentially in the same manner as in Preparative Example 191 and Step B of Example 1 to give the title compound (0.005 g, 12%).

[3544] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.34 (1H, m), 7.03 (3H, m), 4.08 (1H, m), 3.32 (1H, m), 2.62 (2H, t), 2.19 (2H, m), 1.87 (2H, m), 1.71-1.51 (6H, m), 1.30 (3H, d).[3544] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.34 (1H, m), 7.03 (3H, m), 4.08 (1H, m), 3.32 (1H, m), 2.62 (2H, t), 2.19 (2H, m), 1.87 (2H, m), 1.71-1.51 (6H, m), 1.30 (3H, d).

[3546] Primer 203: 4-[4-[2-(2-dimetilaminoetiloksi)-3-piridil]-2,6-difluoro-fenoksi]buterna kiselina [1360][3546] Example 203: 4-[4-[2-(2-dimethylaminoethyloxy)-3-pyridyl]-2,6-difluoro-phenoxy]butyric acid [1360]

[3548] [3548]

[3549] Faza A: etil 4-[4-[2-(2-dimetilaminoetiloksi)-3-piridil]-2,6-difluoro-fenoksi]butanoat[3549] Phase A: ethyl 4-[4-[2-(2-dimethylaminoethyloxy)-3-pyridyl]-2,6-difluoro-phenoxy]butanoate

[3550] 2-[(3-jodo-2-piridil)oksi]-N,N-dimetil-etanamin (0.117 g, 0.4 mmol) dobijen u primeru pripreme 206 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.163 g, 0.44 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.06 g, 37%).[3550] 2-[(3-iodo-2-pyridyl)oxy]-N,N-dimethyl-ethanamine (0.117 g, 0.4 mmol) obtained in preparation example 206 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.163 g, 0.44 mmol) obtained in Preparative Example 2 were used to react in the same manner as in Step A of Example 28 to give the title compound (0.06 g, 37%).

[3551] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.58 (1H, m), 7.22 (2H, m), 6.96 (1H, m), 4.49 (2H, t), 4.21 (2H, t), 4.15 (2H, q), 2.72 (2H, t), 2.59 (2H, t), 2.31 (6H, s), 2.11 (2H, m), 1.27 (3H, t)[3551] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.58 (1H, m), 7.22 (2H, m), 6.96 (1H, m), 4.49 (2H, t), 4.21 (2H, t), 4.15 (2H, q), 2.72 (2H, t), 2.59 (2H, t), 2.31 (6H, s), 2.11 (2H, m), 1.27 (3H, t)

[3553] Faza B: 4-[4-[2-(2-dimetilaminoetiloksi)-3-piridil]-2,6-difluoro-fenoksi] buterna kiselina[3553] Phase B: 4-[4-[2-(2-dimethylaminoethyloxy)-3-pyridyl]-2,6-difluoro-phenoxy] butyric acid

[3554] Etil 4-[4-[2-(2-dimetilaminoetiloksi)-3-piridil]-2,6-difluoro-fenoksi] butanoat (0.06 g, 0.15 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.02 g, 38%).[3554] Ethyl 4-[4-[2-(2-dimethylaminoethyloxy)-3-pyridyl]-2,6-difluoro-phenoxy] butanoate (0.06 g, 0.15 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.02 g, 38%).

[3555] 1H-NMR (MeOH-d<4>) δ 8.14 (1H, m), 7.73 (1H, m), 7.21 (2H, m), 7.08 (1H, m), 4.63 (2H, t), 2.19 (2H, t), 3.23 (2H, t), 2.63 (6H, s), 2.40 (2H, t), 2.02 (2H, m)[3555] 1H-NMR (MeOH-d<4>) δ 8.14 (1H, m), 7.73 (1H, m), 7.21 (2H, m), 7.08 (1H, m), 4.63 (2H, t), 2.19 (2H, t), 3.23 (2H, t), 2.63 (6H, s), 2.40 (2H, t), 2.02 (2H, m)

[3557] Primer 204: 4-[2,6-difluoro-4-(2-propilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina[3557] Example 204: 4-[2,6-difluoro-4-(2-propylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid

[3558][3558]

[3560] [3560]

[3563] Faza A: etil estar 4-[2,6-difluoro-4-(2-propilsulfanil-piridin-3-il)-fenoksi]-buterne kiseline[3563] Phase A: 4-[2,6-difluoro-4-(2-propylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid ethyl ester

[3564] 3-jodo-2-propilsulfanil-piridin (0.114 g, 0.410 mmol) dobijen u primeru pripreme 203 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaboran-2-il)fenoksi]buterne kiseline (0.142 g, 0.383 mmol) dobijen u primeru pripreme 2 su rastvoreni u 2 mL vodenog rastvora 2M natrijumkarbonata i 4 mL 1,2-dimetoksietana, i N<2>gas je dodavan 5 minuta. Dodat je bis(trifenilfosfin)paladijum(II) dihlorid (0.013 g, 0.019 mmol) i proizvod je mešan 16 sati na 80°C. Nakon završetka reakcije, proizvod je razblažen vodom i ekstrahovan etilacetatom. Organski sloj je osušen bezvodnim MgSO<4>i prečišćena hromatografijom na koloni (eluent: EtOAc/Hex = 1/4) da bi se dobilo naslovno jedinjenje (0.113 g, 74 %).[3564] 3-iodo-2-propylsulfanyl-pyridine (0.114 g, 0.410 mmol) obtained in preparation example 203 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy]butyric acid ethyl ester (0.142 g, 0.383 mmol) obtained in preparation example 2 were dissolved in 2 mL of aqueous 2M sodium carbonate solution and 4 mL of 1,2-dimethoxyethane, and N<2> gas was added for 5 minutes. Bis(triphenylphosphine)palladium(II) dichloride (0.013 g, 0.019 mmol) was added and the product was stirred for 16 hours at 80°C. After completion of the reaction, the product was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4 and purified by column chromatography (eluent: EtOAc/Hex = 1/4) to give the title compound (0.113 g, 74 %).

[3565] <1>H-NMR (CDCl<3>) δ 8.42(1H, m), 7.32(1H, m), 7.01(3H, m), 4.22(2H, t), 4.15(2H, q), 3.13(2H, t), 2.58(2H, t), 2.11(2H, m), 1.68(2H, m), 1.25(3H, t), 1.01(3H, t)[3565] <1>H-NMR (CDCl<3>) δ 8.42(1H, m), 7.32(1H, m), 7.01(3H, m), 4.22(2H, t), 4.15(2H, q), 3.13(2H, t), 2.58(2H, t), 2.11(2H, m), 1.68(2H, m), 1.25(3H, t), 1.01(3H, t)

[3567] Faza B: 4-[2,6-difluoro-4-(2-propilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina[3567] Phase B: 4-[2,6-difluoro-4-(2-propylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid

[3568] Etil estar 4-[2,6-difluoro-4-(2-propilsulfanil-piridin-3-il)-fenoksi]-buterne kiseline (0.026 g, 0.065 mmol) dobijen u fazi A je rastvoren u THF-u/MeOH/vodi (1:1:1, 3 mL). Dodat je IN NaOH (12 mg, 0.50 mmol), i proizvod je mešan na sobnoj temperaturi 2 sata. Nakon završetka reakcije, proizvod je koncentrovan pod smanjenim pritiskom, i ostatak je razblažen vodom. pH vodenog sloja je podešena na 2-3 upotrebom IN HCl, i proizvod je ekstrahovan etilacetatom. Organski sloj je osušen bezvodnim MgSO<4>i prečišćen hromatografijom na koloni (eluent: EtOAc/Hex = 1/1) da bi se dobilo naslovno jedinjenje (0.014 g, 58 %).[3568] 4-[2,6-difluoro-4-(2-propylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid ethyl ester (0.026 g, 0.065 mmol) obtained in step A was dissolved in THF/MeOH/water (1:1:1, 3 mL). 1N NaOH (12 mg, 0.50 mmol) was added, and the product was stirred at room temperature for 2 hours. After completion of the reaction, the product was concentrated under reduced pressure, and the residue was diluted with water. The pH of the aqueous layer was adjusted to 2-3 using 1N HCl, and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4 and purified by column chromatography (eluent: EtOAc/Hex = 1/1) to give the title compound (0.014 g, 58 %).

[3569] <1>H-NMR (CDCl<3>) δ 8.43(1H, m), 7.32(1H, m), 7.01(3H, m), 4.26(2H, t), 3.14(2H, t), 2.68(2H, t), 2.14(2H, m), 1.69(2H, m), 1.02(3H, t)[3569] <1>H-NMR (CDCl<3>) δ 8.43(1H, m), 7.32(1H, m), 7.01(3H, m), 4.26(2H, t), 3.14(2H, t), 2.68(2H, t), 2.14(2H, m), 1.69(2H, m), 1.02(3H, t)

[3571] Primer 205: 4-[4-(2-ciklopropilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina[3571] Example 205: 4-[4-(2-cyclopropylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid

[3572][3572]

[3574] [3574]

[3577] 2-ciklopropilsulfanil-3-jodo-piridin (0.06 g, 0.21 mmol) dobijen u primeru pripreme 239 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaboran-2-il)fenoksi]buterne kiseline (0.074 g, 0.202 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u primeru 1 da bi se dobilo naslovno jedinjenje (0.03 g, 38 %).[3577] 2-cyclopropylsulfanyl-3-iodo-pyridine (0.06 g, 0.21 mmol) obtained in preparation example 239 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy]butyric acid ethyl ester (0.074 g, 0.202 mmol) obtained in preparation example 2 were used. to react in the same way as in Example 1 to give the title compound (0.03 g, 38 %).

[3578] <1>H-NMR (CDCl<3>) δ 8.52(1H, m), 7.34(1H, m), 7.09(1H, m), 6.95(2H, m), 4.25(2H, m), 2.67(2H, t), 2.40(1H, m), 2.12(2H, m), 1.07(2H, m), 0.59(2H, m)[3578] <1>H-NMR (CDCl<3>) δ 8.52(1H, m), 7.34(1H, m), 7.09(1H, m), 6.95(2H, m), 4.25(2H, m), 2.67(2H, t), 2.40(1H, m), 2.12(2H, m), 1.07(2H, m), 0.59(2H, m)

[3580] Primer 206: 4-[4-(2-etilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina[3580] Example 206: 4-[4-(2-ethylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid

[3581][3581]

[3583] [3583]

[3586] 2-etilsulfanil-3-jodo-piridin (0.098 g, 0.369 mmol) dobijen u primeru pripreme 240 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaboran-2-il) fenoksi]buterne kiseline (0.127 g, 0.345 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u primeru 1 da bi se dobilo naslovno jedinjenje (0.03 g, 35 %).[3586] 2-Ethylsulfanyl-3-iodo-pyridine (0.098 g, 0.369 mmol) obtained in preparation example 240 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) phenoxy]butyric acid ethyl ester (0.127 g, 0.345 mmol) obtained in preparation example 2 were used to react in the same manner as in Example 1 to give the title compound (0.03 g, 35 %).

[3587] <1>H-NMR (CDCl<3>) δ 8.45(1H, m), 7.34(1H, m), 7.05(1H, m), 6.99(2H, m), 4.26(2H, t), 3.17(2H, q), 2.68(2H, t), 2.13(2H, m), 1.33(3H, t)[3587] <1>H-NMR (CDCl<3>) δ 8.45(1H, m), 7.34(1H, m), 7.05(1H, m), 6.99(2H, m), 4.26(2H, t), 3.17(2H, q), 2.68(2H, t), 2.13(2H, m), 1.33(3H, t)

[3588] Primer 207: 4-[4-(2-butilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina[3588] Example 207: 4-[4-(2-Butylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid

[3589][3589]

[3591] [3591]

[3594] 2-butilsulfanil-3-jodo-piridin (0.102 g, 0.347 mmol) dobijen u primeru pripreme 241 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaboran-2-il)fenoksi]buterne kiseline (0.12 g, 0.325 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u primeru 1 da bi se dobilo naslovno jedinjenje (0.052 g, 39 %).[3594] 2-Butylsulfanyl-3-iodo-pyridine (0.102 g, 0.347 mmol) obtained in Preparation Example 241 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy]butyric acid ethyl ester (0.12 g, 0.325 mmol) obtained in Preparation Example 2 were used. to react in the same way as in Example 1 to give the title compound (0.052 g, 39 %).

[3595] <1>H-NMR (CDCl<3>) δ 8.43(1H, m), 7.33(1H, d), 7.04(1H, m), 6.99(2H, m), 4.26(2H, t), 3.17(2H, t), 2.68(2H, t), 2.14(2H, m), 1.66(2H, m), 1.44(2H, m), 0.93(3H, t)[3595] <1>H-NMR (CDCl<3>) δ 8.43(1H, m), 7.33(1H, d), 7.04(1H, m), 6.99(2H, m), 4.26(2H, t), 3.17(2H, t), 2.68(2H, t), 2.14(2H, m), 1.66(2H, m), 1.44(2H, m), 0.93(3H, t)

[3597] Primer 208: 4-(2'-ciklopentilamino-bifenil-4-ilsulfanil)-buterna kiselina.[3597] Example 208: 4-(2'-cyclopentylamino-biphenyl-4-ylsulfanyl)-butyric acid.

[3598][3598]

[3600] [3600]

[3603] Etil estar 4-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 159 i n-ciklopentil-2-jodo-anilin (0.045 g, 0.16 mmol) dobijen u primeru pripreme 70 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.02 g, 40%).[3603] 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 159 and n-cyclopentyl-2-iodo-aniline (0.045 g, 0.16 mmol) obtained in Preparation Example 70 were used to reacted in the same manner as in steps A and B of Example 1 to give the title compound (0.02 g, 40%).

[3604] <1>H-NMR (CDCl<3>) δ 7.39 (2H, d), 7.33 (2H, d), 7.21 (1H, t), 7.03 (1H, m), 6.72 (2H, m), 3.77 (1H, m), 3.03 (2H, t), 2.56 (2H, t), 2.03-1.95 (4H, m), 1.61 (4H, m), 1.38 (2H, m).[3604] <1>H-NMR (CDCl<3>) δ 7.39 (2H, d), 7.33 (2H, d), 7.21 (1H, t), 7.03 (1H, m), 6.72 (2H, m), 3.77 (1H, m), 3.03 (2H, t), 2.56 (2H, t), 2.03-1.95 (4H, m), 1.61 (4H, m), 1.38 (2H, m).

[3606] Primer 209: 4-[4-(2-ciklopentiloksi-5-metil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina [1382][3606] Example 209: 4-[4-(2-cyclopentyloxy-5-methyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid [1382]

[3608] [3608]

[3610] Etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.05 g, 0.13 mmol) dobijen u primeru pripreme 2 i 3-bromo-2-ciklopentiloksi-5-metil-piridin (0.05 g, 0.20 mmol) dobijen u primeru pripreme 131 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.027 g, 52%).[3610] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.05 g, 0.13 mmol) obtained in preparation example 2 and 3-bromo-2-cyclopentyloxy-5-methyl-pyridine (0.05 g, 0.20 mmol) obtained in preparation example 131 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.027 g, 52%).

[3611] <1>H-NMR (CDCl<3>) δ 7.95 (1H, s), 7.39 (1H, s), 7.12 (2H, d), 5.46 (1H, m), 4.22 (2H, t), 2.66 (2H, t), 2.27 (3H, s), 2.12 (2H, m), 1.92 (2H, m), 1.80-1.72 (4H, m), 1.62 (2H, m).[3611] <1>H-NMR (CDCl<3>) δ 7.95 (1H, s), 7.39 (1H, s), 7.12 (2H, d), 5.46 (1H, m), 4.22 (2H, t), 2.66 (2H, t), 2.27 (3H, s), 2.12 (2H, m), 1.92 (2H, m), 1.80-1.72 (4H, m), 1.62 (2H, m).

[3613] Primer 210: 4-[4-(6-izopropilsulfanil-2-piridil)fenoksi]buterna kiselina[3613] Example 210: 4-[4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]butyric acid

[3614][3614]

[3616] [3616]

[3619] Faza A: etil 4-[4-(6-izopropilsulfanil-2-piridil)fenoksi]butanoat[3619] Phase A: ethyl 4-[4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]butanoate

[3620] Etil estar 4-[4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.143 g, 0.43mmol) dobijen u primeru pripreme 1 i 2-hloro-6-izopropilsulfanil-piridin (0.03 g, 0.16 mmol) dobijen u primeru pripreme 125 su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.036 g, 62%).[3620] 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.143 g, 0.43 mmol) obtained in Preparation Example 1 and 2-chloro-6-isopropylsulfanyl-pyridine (0.03 g, 0.16 mmol) obtained in Preparation Example 125 were used to react in the same manner as in Step A of Example 29 to give the title compound (0.036 g, 62%).

[3621] 1H NMR (CDCl<3>) δ 7.97 (2H, d), 7.48 (1H, t), 7.35 (1H, d), 7.02 (1H, d), 6.95 (2H, d), 4.14 (3H, m), 4.07 (2H, t), 2.53 (2H, t), 2.14 (2H, m), 1.46 (6H, d), 1.26 (3H, t)[3621] 1H NMR (CDCl<3>) δ 7.97 (2H, d), 7.48 (1H, t), 7.35 (1H, d), 7.02 (1H, d), 6.95 (2H, d), 4.14 (3H, m), 4.07 (2H, t), 2.53 (2H, t), 2.14 (2H, m), 1.46 (6H, d), 1.26 (3H, t)

[3623] Faza B: 4-[4-(6-izopropilsulfanil-2-piridil)fenoksi]buterna kiselina[3623] Phase B: 4-[4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]butyric acid

[3624] Etil 4-[4-(6-izopropilsulfanil-2-piridil)fenoksi]butanoat (0.036 g, 0.1 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.019 g, 57%).[3624] Ethyl 4-[4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]butanoate (0.036 g, 0.1 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.019 g, 57%).

[3625] 1H NMR (CDCl<3>) δ 7.98 (2H, d), 7.48 (1H, t), 7.35 (1H, m), 7.02 (1H, m), 6.96 (2H, m), 4.16 (1H, m), 4.09 (2H, t), 2.61 (2H, t), 2.14 (2H, m), 1.46 (6H, d)[3625] 1H NMR (CDCl<3>) δ 7.98 (2H, d), 7.48 (1H, t), 7.35 (1H, m), 7.02 (1H, m), 6.96 (2H, m), 4.16 (1H, m), 4.09 (2H, t), 2.61 (2H, t), 2.14 (2H, m), 1.46 (6H, d)

[3627] Primer 211: 4-[2,6-difluoro-4-(3-fenoksifenil)fenoksi]buterna kiselina[3627] Example 211: 4-[2,6-difluoro-4-(3-phenoxyphenyl)phenoxy]butyric acid

[3628][3628]

[3630] [3630]

[3633] Etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.090 g, 0.24 mmol) dobijen u primeru pripreme 2 i 1-bromo-3-fenoksi-benzen (0.06 g.0.24 mmol) su korišćeni da bi reagovali na isti način kao u fazama A i B primera 29 da bi se dobilo naslovno jedinjenje (0.078 g, 80%).[3633] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.090 g, 0.24 mmol) obtained in Preparation Example 2 and 1-bromo-3-phenoxy-benzene (0.06 g, 0.24 mmol) were used to react in the same manner as in steps A and B of Example 29 to give the title compound (0.078 g, 80%).

[3634] 1H NMR (CDCl<3>) δ 7.36 (3H, m), 7.23 (1H, m), 7.13 (2H, m), 7.08 (2H, m), 7.04 (2H, m), 6.99 (1H, m), 4.21 (2H, t), 2.66 (2H, t), 2.11 (2H, m)[3634] 1H NMR (CDCl<3>) δ 7.36 (3H, m), 7.23 (1H, m), 7.13 (2H, m), 7.08 (2H, m), 7.04 (2H, m), 6.99 (1H, m), 4.21 (2H, t), 2.66 (2H, t), 2.11 (2H, m)

[3636] Primer 212: 4-[4-[6-[3-(dimetilamino)pirolidin-1-il]-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina [1393][3636] Example 212: 4-[4-[6-[3-(dimethylamino)pyrrolidin-1-yl]-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid [1393]

[3638] [3638]

[3641] 1-(6-hloro-2-piridil)-N,N-dimetil-pirolidin-3-amin (0.04 g, 0.18mmol) dobijen u primeru pripreme 124 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.066 g, 0.18 mmol) dobijen u primeru pripreme 2 su korišćeni da bi sekvencijalno reagovali na isti način kao u fazi A primera 29 i fazi B primera 1 da bi se dobilo naslovno jedinjenje (3.3 mg, 5%).[3641] 1-(6-chloro-2-pyridyl)-N,N-dimethyl-pyrrolidin-3-amine (0.04 g, 0.18 mmol) obtained in Preparation Example 124 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.066 g, 0.18 mmol) obtained in Preparative Example 2 were used to react sequentially in the same manner as in Phase A of Example 29 and Phase B of Example 1 to give the title compound (3.3 mg, 5%).

[3642] 1H NMR (CDCl<3>) δ 7.43 (3H, m), 6.88 (1H, m), 6.31 (1H, m), 4.21 (2H, t), 3.85 (1H, m), 3.74 (1H, m), 3.48 (2H, m), 3.17 (1H, m), 2.56 (2H, t), 2.47 (6H, s), 2.27 (1H, m), 2.24 (1H, m), 2.08 (2H, m)[3642] 1H NMR (CDCl<3>) δ 7.43 (3H, m), 6.88 (1H, m), 6.31 (1H, m), 4.21 (2H, t), 3.85 (1H, m), 3.74 (1H, m), 3.48 (2H, m), 3.17 (1H, m), 2.56 (2H, t), 2.47 (6H, s), 2.27 (1H, m), 2.24 (1H, m), 2.08 (2H, m)

[3644] Primer 213: 5-[2,6-difluoro-4-(2-izopropoksi-piridin-3-il)-fenoksi]-valerijanska kiselina[3644] Example 213: 5-[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenoxy]-valeric acid

[3645][3645]

[3647] [3647]

[3650] 3-jodo-2-izopropoksi-piridin (0.040 g, 0.15 mmol) dobijen u primeru pripreme 37 i etil 5-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]pentanoat (0.058 g, 0.15 mmol) dobijen u primeru pripreme 225 su korišćeni da bi reagovali na isti način kao u primeru 1 da bi se dobilo naslovno jedinjenje (0.038 g, 68 %).[3650] 3-Iodo-2-isopropoxy-pyridine (0.040 g, 0.15 mmol) obtained in Preparation Example 37 and ethyl 5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pentanoate (0.058 g, 0.15 mmol) obtained in Preparation Example 225 were used to would react in the same way as in example 1 to obtain the title compound (0.038 g, 68 %).

[3651] 1H NMR (CDCl<3>) 8.13 (1H, m), 7.56 (1H, m), 7.16 (2H, m), 6.92 (1H, m), 5.41 (1H, m), 4.20 (2H, t), 2.49 (2H, t), 1.89 (4H, m), 1.36 (6H, d)[3651] 1H NMR (CDCl<3>) 8.13 (1H, m), 7.56 (1H, m), 7.16 (2H, m), 6.92 (1H, m), 5.41 (1H, m), 4.20 (2H, t), 2.49 (2H, t), 1.89 (4H, m), 1.36 (6H, d)

[3653] Primer 214: 5-[4-(2-ciklobutoksi-piridin-3-il)-2,6-difluoro-fenoksi]-valerijanska kiselina[3653] Example 214: 5-[4-(2-cyclobutoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-valeric acid

[3654][3654]

[3656] [3656]

[3657] 2-ciklobutoksi-3-jodo-piridin (0.040 g, 0.15 mmol) dobijen u primeru pripreme 200 i etil 5-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]pentanoat (0.056 g, 0.15 mmol) dobijen u primeru pripreme 225 su korišćeni da bi reagovali na isti način kao u primeru 1 da bi se dobilo naslovno jedinjenje (0.033 g, 60 %).[3657] 2-cyclobutoxy-3-iodo-pyridine (0.040 g, 0.15 mmol) obtained in Preparation Example 200 and ethyl 5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pentanoate (0.056 g, 0.15 mmol) obtained in Preparation Example 225 were used. to react in the same way as in Example 1 to give the title compound (0.033 g, 60 %).

[3658] 1H NMR (CDCl<3>) 8.12 (1H, m), 7.57 (1H, m), 7.18 (2H, m), 6.94 (1H, m), 5.28 (1H, m), 4.20 (2H, t), 2.48 (4H, m), 2.13 (2H, m), 1.89 (5H, m), 1.72 (1H, m)[3658] 1H NMR (CDCl<3>) 8.12 (1H, m), 7.57 (1H, m), 7.18 (2H, m), 6.94 (1H, m), 5.28 (1H, m), 4.20 (2H, t), 2.48 (4H, m), 2.13 (2H, m), 1.89 (5H, m), 1.72 (1H, m)

[3660] Primer 215: 4-[4-[2-(3,3-difluoropirolidin-1-il)-3-piridil]-2,6-difluoro-fenoksi]buterna kiselina [1402][3660] Example 215: 4-[4-[2-(3,3-difluoropyrrolidin-1-yl)-3-pyridyl]-2,6-difluoro-phenoxy]butyric acid [1402]

[3662] [3662]

[3665] Faza A: etil 4-[4-[2-(3,3-difluoropirolidin-1-il)-3-piridil]-2,6-difluoro-12henoksi]butanoat[3665] Phase A: ethyl 4-[4-[2-(3,3-difluoropyrrolidin-1-yl)-3-pyridyl]-2,6-difluoro-12henoxy]butanoate

[3666] Etil 4-[2,6-difluoro-4-(2-fluoro-3-piridil)fenoksi]butanoat (0.09 g, 0.27 mmol) dobijen u primeru pripreme 109 i 3,3-difluoropirolidin hidrohlorid (0.11 g, 0.8 mmol) su korišćeni da bi reagovali na isti način kao u fazi A primera 72 da bi se dobilo naslovno jedinjenje (0.007 g, 6%).[3666] Ethyl 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butanoate (0.09 g, 0.27 mmol) obtained in Preparative Example 109 and 3,3-difluoropyrrolidine hydrochloride (0.11 g, 0.8 mmol) were used to react in the same manner as in Step A of Example 72 to give the title compound. (0.007 g, 6%).

[3667] 1H NMR (CDCl<3>) δ 8.20 (1H, m), 7.38 (1H, m), 6.98 (2H, m), 6.84 (1H, m), 4.24 (2H, t), 4.16 (2H, q), 4.45 (4H, m), 2.59 (2H, t), 2.27 (2H, m), 2.13 (2H, m), 1.27 (3H, t)[3667] 1H NMR (CDCl<3>) δ 8.20 (1H, m), 7.38 (1H, m), 6.98 (2H, m), 6.84 (1H, m), 4.24 (2H, t), 4.16 (2H, q), 4.45 (4H, m), 2.59 (2H, t), 2.27 (2H, m), 2.13 (2H, m), 1.27 (3H, t)

[3669] Faza B: 4-[4-[2-(3,3-difluoropirolidin-1-il)-3-piridil]-2,6-difluoro-fenoksi] buterna kiselina[3669] Phase B: 4-[4-[2-(3,3-difluoropyrrolidin-1-yl)-3-pyridyl]-2,6-difluoro-phenoxy] butyric acid

[3670] Etil 4-[4-[2-(3,3-difluoropirolidin-1-il)-3-piridil]-2,6-difluoro-fenoksi] butanoat (0.007 g, 0.016 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.006 g, 98%).[3670] Ethyl 4-[4-[2-(3,3-difluoropyrrolidin-1-yl)-3-pyridyl]-2,6-difluoro-phenoxy] butanoate (0.007 g, 0.016 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.006 g, 98%).

[3671] 1H NMR (CDCl<3>) δ 8.21 (1H, m), 7.38 (1H, m), 6.95 (2H, m), 6.8 (1H, m), 4.25 (2H, t), 3.43 (4H, m), 2.68 (2H, t), 2.28 (2H, m), 2.14 (2H, m)[3671] 1H NMR (CDCl<3>) δ 8.21 (1H, m), 7.38 (1H, m), 6.95 (2H, m), 6.8 (1H, m), 4.25 (2H, t), 3.43 (4H, m), 2.68 (2H, t), 2.28 (2H, m), 2.14 (2H, m)

[3673] Primer 216: 4-[2,6-difluoro-4-[2-(4-metilpiperazin-1-il)-3-piridil] fenoksi]buterna kiselina[3673] Example 216: 4-[2,6-difluoro-4-[2-(4-methylpiperazin-1-yl)-3-pyridyl] phenoxy]butyric acid

[3674][3674]

[3676] [3676]

[3677] Faza A: etil 4-[2,6-difluoro-4-[2-(4-metilpiperazin-1-il)-3-piridil]fenoksi] butanoat[3677] Phase A: Ethyl 4-[2,6-difluoro-4-[2-(4-methylpiperazin-1-yl)-3-pyridyl]phenoxy] butanoate

[3678] Etil 4-[2,6-difluoro-4-(2-fluoro-3-piridil)fenoksi]butanoat (0.09 g, 0.27 mmol) dobijen u primeru pripreme 109 i 1-metilpiperazin (0.088 g, 0.8 mmol) su korišćeni da bi reagovali na isti način kao u fazi A primera 72 da bi se dobilo naslovno jedinjenje (0.007 g, 6%).[3678] Ethyl 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butanoate (0.09 g, 0.27 mmol) obtained in Preparative Example 109 and 1-methylpiperazine (0.088 g, 0.8 mmol) were used to react in the same manner as in Step A of Example 72 to give the title compound (0.007 g, 6%).

[3679] 1H NMR (CDCl<3>) δ 8.23 (1H, m), 7.38 (1H, m), 7.16 (2H, m), 6.92 (1H, m), 4.23 (2H, t), 4.17 (2H, q), 3.14 (4H, m), 2.60 (2H, t), 2.40 (4H, m), 2.30 (3H, s), 2.11 (2H, m), 1.27 (3H, t)[3679] 1H NMR (CDCl<3>) δ 8.23 (1H, m), 7.38 (1H, m), 7.16 (2H, m), 6.92 (1H, m), 4.23 (2H, t), 4.17 (2H, q), 3.14 (4H, m), 2.60 (2H, t), 2.40 (4H, m), 2.30 (3H, s), 2.11 (2H, m), 1.27 (3H, t)

[3681] Faza B: 4-[2,6-difluoro-4-[2-(4-metilpiperazin-1-il)-3-piridil]fenoksi] buterna kiselina[3681] Phase B: 4-[2,6-difluoro-4-[2-(4-methylpiperazin-1-yl)-3-pyridyl]phenoxy] butyric acid

[3682] Etil 4-[2,6-difluoro-4-[2-(4-metilpiperazin-1-il)-3-piridil]fenoksi] butanoat (0.007 g, 0.016 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.0013 g, 20%).[3682] Ethyl 4-[2,6-difluoro-4-[2-(4-methylpiperazin-1-yl)-3-pyridyl]phenoxy] butanoate (0.007 g, 0.016 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.0013 g, 20%).

[3683] 1H NMR (CDCl<3>) δ 8.21 (1H, m), 7.40 (1H, m), 7.08 (2H, m), 6.91 (1H, m), 4.26 (2H, t), 3.23 (4H, m), 2.62 (4H, m), 2.52 (2H, t), 2.39 (3H, s), 2.07 (2H, m)[3683] 1H NMR (CDCl<3>) δ 8.21 (1H, m), 7.40 (1H, m), 7.08 (2H, m), 6.91 (1H, m), 4.26 (2H, t), 3.23 (4H, m), 2.62 (4H, m), 2.52 (2H, t), 2.39 (3H, s), 2.07 (2H, m)

[3685] Primer 217: 4-[2,6-difluoro-4-[2-(5-metilisoksazol-3-il)oksi-3-piridil] fenoksi]buterna kiselina [1412][3685] Example 217: 4-[2,6-difluoro-4-[2-(5-methylisoxazol-3-yl)oxy-3-pyridyl]phenoxy]butyric acid [1412]

[3687] [3687]

[3690] Faza A: etil 4-[2,6-difluoro-4-[2-(5-metilisoksazol-3-il)oksi-3-piridil] fenoksi]butanoat[3690] Phase A: ethyl 4-[2,6-difluoro-4-[2-(5-methylisoxazol-3-yl)oxy-3-pyridyl] phenoxy]butanoate

[3691] 3-[(3-jodo-2-piridil)oksi]-5-metil-isoksazol (0.15 g, 0.5 mmol) dobijen u primeru pripreme 205 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.20 g, 0.54 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.14 g, 67%).[3691] 3-[(3-iodo-2-pyridyl)oxy]-5-methylisoxazole (0.15 g, 0.5 mmol) obtained in preparation example 205 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.20 g, 0.54 mmol) obtained in example Preparation 2 was used to react in the same manner as in Step A of Example 28 to give the title compound (0.14 g, 67%).

[3692] <1>H-NMR (CDCl<3>) δ 8.21 (1H, m), 7.75 (1H, m), 7.20 (3H, m), 6.02 (1H, s), 4.23 (2H, t), 4.15 (2H, q), 2.58 (2H, t), 2.43 (3H, s), 2.12 (2H, m), 1.27 (3H, t)[3692] <1>H-NMR (CDCl<3>) δ 8.21 (1H, m), 7.75 (1H, m), 7.20 (3H, m), 6.02 (1H, s), 4.23 (2H, t), 4.15 (2H, q), 2.58 (2H, t), 2.43 (3H, s), 2.12 (2H, m), 1.27 (3H, t)

[3694] Faza B: 4-[2,6-difluoro-4-[2-(5-metilisoksazol-3-il)oksi-3-piridil]fenoksi] buterna kiselina[3694] Phase B: 4-[2,6-difluoro-4-[2-(5-methylisoxazol-3-yl)oxy-3-pyridyl]phenoxy]butyric acid

[3695] Etil 4-[2,6-difluoro-4-[2-(5-metilisoksazol-3-il)oksi-3-piridil]fenoksi] butanoat (0.14 g, 0.33 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.1 g, 78%).[3695] Ethyl 4-[2,6-difluoro-4-[2-(5-methylisoxazol-3-yl)oxy-3-pyridyl]phenoxy] butanoate (0.14 g, 0.33 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.1 g, 78%).

[3696] <1>H-NMR (CDCl<3>) δ 8.21 (1H, m), 7.74 (1H, m), 7.17 (3H, m), 6.02 (1H, s), 4.25 (2H, t), 2.67 (2H, t), 2.43 (3H, s), 2.12 (2H, m)[3696] <1>H-NMR (CDCl<3>) δ 8.21 (1H, m), 7.74 (1H, m), 7.17 (3H, m), 6.02 (1H, s), 4.25 (2H, t), 2.67 (2H, t), 2.43 (3H, s), 2.12 (2H, m)

[3697] Primer 218: 4-[4-[2-[2-(aziridin-1-il)etoksil-3-piridil]-2,6-difluoro-fenoksi]buterna kiselina[3697] Example 218: 4-[4-[2-[2-(aziridin-1-yl)ethoxyl-3-pyridyl]-2,6-difluoro-phenoxy]butyric acid

[3698][3698]

[3700] [3700]

[3703] 2-[2-(aziridin-1-il)etoksi]-3-jodo-piridin (0.095 g, 0.33 mmol) dobijen u primeru pripreme 207 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.133 g, 0.36 mmol) dobijen u primeru pripreme 2 su korišćeni da bi sekvencijalno reagovali na isti način kao u fazi A primera 28 i fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.001 g, 0.1%).[3703] 2-[2-(aziridin-1-yl)ethoxy]-3-iodo-pyridine (0.095 g, 0.33 mmol) obtained in preparation example 207 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.133 g, 0.36 mmol) obtained in Preparative Example 2 were used to react sequentially in the same manner as in Phase A of Example 28 and Phase B of Example 1 to obtain the title compound (0.001 g, 0.1%).

[3704] 1H-NMR (MeOH-d4) δ 8.11 (1H, m), 7.72 (1H, m), 7.25 (2H, m), 7.04 (1H, m), 4.51 (2H, m), 4.18 (2H, t), 2.67 (2H, t), 2.45 (2H, t), 2.02 (2H, m), 1.73 (2H, m), 1.34 (2H, m)[3704] 1H-NMR (MeOH-d4) δ 8.11 (1H, m), 7.72 (1H, m), 7.25 (2H, m), 7.04 (1H, m), 4.51 (2H, m), 4.18 (2H, t), 2.67 (2H, t), 2.45 (2H, t), 2.02 (2H, m), 1.73 (2H, m), 1.34 (2H, m)

[3706] Primer 219: 4-[2,6-difluoro-4-[2-(furilmetoksi)-3-piridil]fenoksi] buterna kiselina[3706] Example 219: 4-[2,6-difluoro-4-[2-(furylmethoxy)-3-pyridyl]phenoxy]butyric acid

[3707][3707]

[3709] [3709]

[3712] Faza A: etil 4-[2,6-difluoro-4-[2-(furilmetoksi)-3-piridil]fenoksi]butanoat[3712] Phase A: ethyl 4-[2,6-difluoro-4-[2-(furylmethoxy)-3-pyridyl]phenoxy]butanoate

[3713] 2-(furilmetoksi)-3-jodo-piridin (0.107 g, 0.36 mmol) dobijen u primeru pripreme 208 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.10 g, 0.27 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.058 g, 51%).[3713] 2-(Furylmethoxy)-3-iodo-pyridine (0.107 g, 0.36 mmol) obtained in Preparation Example 208 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.10 g, 0.27 mmol) obtained in Preparation Example 2 were used to would react in the same manner as in step A of Example 28 to give the title compound (0.058 g, 51%).

[3714] <1>H-NMR (CDCl<3>) δ 8.17 (1H, m), 7.59 (1H, m), 7.48 (1H, m), 7.40 (1H, m), 7.14 (2H, m), 6.98 (1H, m), 6.47 (1H, m), 5.34 (2H, s), 4.21 (2H, t), 4.15 (2H, q), 2.58 (2H, t), 2.10 (2H, m), 1.27 (3H, t)[3714] <1>H-NMR (CDCl<3>) δ 8.17 (1H, m), 7.59 (1H, m), 7.48 (1H, m), 7.40 (1H, m), 7.14 (2H, m), 6.98 (1H, m), 6.47 (1H, m), 5.34 (2H, s), 4.21 (2H, t), 4.15 (2H, q), 2.58 (2H, t), 2.10 (2H, m), 1.27 (3H, t)

[3716] Faza B: 4-[2,6-difluoro-4-[2-(furilmetoksi)-3-piridil]fenoksi]buterna kiselina[3716] Phase B: 4-[2,6-difluoro-4-[2-(furylmethoxy)-3-pyridyl]phenoxy]butyric acid

[3717] Etil 4-[2,6-difluoro-4-[2-(furilmetoksi)-3-piridil]fenoksi]butanoat (0.058 g, 0.14 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.054 g, 99%).[3717] Ethyl 4-[2,6-difluoro-4-[2-(furylmethoxy)-3-pyridyl]phenoxy]butanoate (0.058 g, 0.14 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.054 g, 99%).

[3718] <1>H-NMR (CDCl<3>) δ 8.18 (1H, m), 7.59 (1H, m), 7.48 (1H, m), 7.41 (1H, m), 7.14 (2H, m), 6.98 (1H, m), 6.47 (1H, m), 5.33 (2H, s), 4.23 (2H, t), 2.67 (2H, t), 2.11 (2H, m)[3718] <1>H-NMR (CDCl<3>) δ 8.18 (1H, m), 7.59 (1H, m), 7.48 (1H, m), 7.41 (1H, m), 7.14 (2H, m), 6.98 (1H, m), 6.47 (1H, m), 5.33 (2H, s), 4.23 (2H, t), 2.67 (2H, t), 2.11 (2H, m)

[3719] Primer 220: 4-[2,6-difluoro-4-[2-(2-furilmetoksi)-3-piridil]fenoksi] buterna kiselina[3719] Example 220: 4-[2,6-difluoro-4-[2-(2-furylmethoxy)-3-pyridyl]phenoxy]butyric acid

[3720][3720]

[3722] [3722]

[3725] Faza A: etil 4-[2.6-difluoro-4-[2-(2-furilmetoksi)-3-piridil]fenoksi]butanoat[3725] Phase A: ethyl 4-[2,6-difluoro-4-[2-(2-furylmethoxy)-3-pyridyl]phenoxy]butanoate

[3726] 2-(2-furilmetoksi)-3-jodo-piridin (0.12 g, 0.4 mmol) dobijen u primeru pripreme 209 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.18 g, 0.49 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.108 g, 65%).[3726] 2-(2-Furylmethoxy)-3-iodo-pyridine (0.12 g, 0.4 mmol) obtained in Preparation Example 209 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.18 g, 0.49 mmol) obtained in Preparation Example 2 were used to would react in the same manner as in step A of Example 28 to give the title compound (0.108 g, 65%).

[3727] <1>H-NMR (CDCl<3>) δ 8.17 (1H, m), 7.59 (1H, m), 7.23 (1H, m), 7.13 (2H, m), 7.00 (1H, m), 6.41 (1H, m), 6.35 (1H, m), 5.42 (2H, s), 4.20 (2H, m), 4.14 (2H, q), 2.57 (2H, t), 2.10 (2H, m), 1.27 (3H, t)[3727] <1>H-NMR (CDCl<3>) δ 8.17 (1H, m), 7.59 (1H, m), 7.23 (1H, m), 7.13 (2H, m), 7.00 (1H, m), 6.41 (1H, m), 6.35 (1H, m), 5.42 (2H, s), 4.20 (2H, m), 4.14 (2H, q), 2.57 (2H, t), 2.10 (2H, m), 1.27 (3H, t)

[3729] Faza B: 4-[2,6-difluoro-4-[2-(2-furilmetoksi)-3-piridil]fenoksi]buterna kiselina[3729] Phase B: 4-[2,6-difluoro-4-[2-(2-furylmethoxy)-3-pyridyl]phenoxy]butyric acid

[3730] Etil 4-[2,6-difluoro-4-[2-(2-furilmetoksi)-3-piridil]fenoksi]butanoat (0.108 g, 0.26 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.077 g, 76%).[3730] Ethyl 4-[2,6-difluoro-4-[2-(2-furylmethoxy)-3-pyridyl]phenoxy]butanoate (0.108 g, 0.26 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.077 g, 76%).

[3731] <1>H-NMR (CDCl<3>) δ 8.17 (1H, m), 7.58 (1H, m), 7.43 (1H, m), 7.14 (2H, m), 7.00 (1H, m), 6.42 (1H, m), 6.35 (1H, m), 5.42 (2H, s), 4.21 (2H, t), 2.66 (2H, t), 2.10 (2H, m)[3731] <1>H-NMR (CDCl<3>) δ 8.17 (1H, m), 7.58 (1H, m), 7.43 (1H, m), 7.14 (2H, m), 7.00 (1H, m), 6.42 (1H, m), 6.35 (1H, m), 5.42 (2H, s), 4.21 (2H, t), 2.66 (2H, t), 2.10 (2H, m)

[3733] Primer 221: 4-[2,6-difluoro-4-[2-[(3-metiloksetan-3-il)metoksi]-3-piridil]fenoksi]buterna kiselina [1430][3733] Example 221: 4-[2,6-difluoro-4-[2-[(3-methyloxetan-3-yl)methoxy]-3-pyridyl]phenoxy]butyric acid [1430]

[3735] [3735]

[3738] aza A: etil 4-[2,6-difluoro-4-[2-[(3-metiloksetan-3-il)metoksi]-3-piridil] fenoksi]butanoat[3738] aza A: ethyl 4-[2,6-difluoro-4-[2-[(3-methyloxetan-3-yl)methoxy]-3-pyridyl] phenoxy]butanoate

[3739] 3-jodo-2-[(3-metiloksetan-3-il)metoksi]piridin (0.12 g, 0.4 mmol) dobijen u primeru pripreme 210 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.18 g, 0.49 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.10 g, 59%).[3739] 3-Iodo-2-[(3-methyloxetan-3-yl)methoxy]pyridine (0.12 g, 0.4 mmol) obtained in Preparation Example 210 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.18 g, 0.49 mmol) obtained in Example Preparation 2 was used to react in the same manner as in Step A of Example 28 to give the title compound (0.10 g, 59%).

[3740] <1>H-NMR (CDCl<3>) δ 8.15 (1H, m), 7.61 (1H, m), 7.15 (2H, m), 7.00 (1H, m), 4.58 (2H, d), 4.48 (2H, s), 4.42 (2H, d), 4.23 (2H, t), 4.16 (2H, q), 2.59 (2H, t), 2.11 (2H, m), 1.39 (3H, s), 1.27 (3H, t)[3740] <1>H-NMR (CDCl<3>) δ 8.15 (1H, m), 7.61 (1H, m), 7.15 (2H, m), 7.00 (1H, m), 4.58 (2H, d), 4.48 (2H, s), 4.42 (2H, d), 4.23 (2H, t), 4.16 (2H, q), 2.59 (2H, t), 2.11 (2H, m), 1.39 (3H, s), 1.27 (3H, t)

[3742] Faza B: 4-[2,6-difluoro-4-[2-[(3-metiloksetan-3-il)metoksil-3-piridil] fenoksi]buterna kiselina [1433] Etil 4-[2,6-difluoro-4-[2-[(3-metiloksetan-3-il)metoksi]-3-piridil]fenoksi] butanoat (0.10 g, 0.24 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.047 g, 48%).[3742] Phase B: 4-[2,6-difluoro-4-[2-[(3-methyloxetan-3-yl)methoxyl-3-pyridyl]phenoxy]butyric acid [1433] Ethyl 4-[2,6-difluoro-4-[2-[(3-methyloxetan-3-yl)methoxy]-3-pyridyl]phenoxy]butanoate (0.10 g, 0.24 mmol) was obtained in Phase A. used to react in the same manner as in Step B of Example 1 to give the title compound (0.047 g, 48%).

[3743] <1>H-NMR (CDCl<3>) δ 8.15 (1H, m), 7.60 (1H, m), 7.13 (2H, m), 7.00 (1H, m), 4.62 (2H, d), 4.43 (4H, m), 4.27 (2H, t), 2.63 (2H, t), 2.10 (2H, m), 1.40 (3H, s)[3743] <1>H-NMR (CDCl<3>) δ 8.15 (1H, m), 7.60 (1H, m), 7.13 (2H, m), 7.00 (1H, m), 4.62 (2H, d), 4.43 (4H, m), 4.27 (2H, t), 2.63 (2H, t), 2.10 (2H, m), 1.40 (3H, s)

[3745] Primer 222: 4-[2,6-difluoro-4-[2-(tetrahidrofuran-3-ilmetoksi)-3-piridil]fenoksi]buterna kiselina [1435][3745] Example 222: 4-[2,6-difluoro-4-[2-(tetrahydrofuran-3-ylmethoxy)-3-pyridyl]phenoxy]butyric acid [1435]

[3747] [3747]

[3750] Faza A: etil 4-[2,6-difluoro-4-[2-(tetrahidrofuran-3-ilmetoksi)-3-piridil] fenoksi]butanoat[3750] Phase A: ethyl 4-[2,6-difluoro-4-[2-(tetrahydrofuran-3-ylmethoxy)-3-pyridyl] phenoxy]butanoate

[3751] 3-jodo-2-(tetrahidrofuran-3-ilmetoksi)piridin (0.12 g, 0.4 mmol) dobijen u primeru pripreme 211 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.18 g, 0.49 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.15 g, 89%).[3751] 3-iodo-2-(tetrahydrofuran-3-ylmethoxy)pyridine (0.12 g, 0.4 mmol) obtained in preparation example 211 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.18 g, 0.49 mmol) obtained in preparation example 2 were used to react in the same manner as in Step A of Example 28 to give the title compound (0.15 g, 89%).

[3752] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.59 (1H, m), 7.13 (2H, m), 6.98 (1H, m), 4.38 (1H, m), 4.28 (1H, m), 4.22 (2H, t), 4.16 (2H, q), 3.88 (2H, m), 3.78 (1H, m), 3.65 (1H, m), 2.75 (1H, m), 2.59 (2H, t), 2.11 (3H, m), 1.73 (1H, m), 1.27 (3H, t)[3752] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.59 (1H, m), 7.13 (2H, m), 6.98 (1H, m), 4.38 (1H, m), 4.28 (1H, m), 4.22 (2H, t), 4.16 (2H, q), 3.88 (2H, m), 3.78 (1H, m), 3.65 (1H, m), 2.75 (1H, m), 2.59 (2H, t), 2.11 (3H, m), 1.73 (1H, m), 1.27 (3H, t)

[3754] Faza B: 4-[2,6-difluoro-4-[2-(tetrahidrofuran-3-ilmetoksi)-3-piridil]fenoksi] buterna kiselina [1438] Etil 4-[2,6-difluoro-4-[2-(tetrahidrofuran-3-ilmetoksi)-3-piridil]fenoksi] butanoat (0.15 g, 0.36 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.11 g, 79%).[3754] Phase B: 4-[2,6-difluoro-4-[2-(tetrahydrofuran-3-ylmethoxy)-3-pyridyl]phenoxy] butyric acid [1438] Ethyl 4-[2,6-difluoro-4-[2-(tetrahydrofuran-3-ylmethoxy)-3-pyridyl]phenoxy] butanoate (0.15 g, 0.36 mmol) obtained in Phase A was used to react in the same manner. as in step B of Example 1 to give the title compound (0.11 g, 79%).

[3755] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.58 (1H, m), 7.11 (2H, m), 6.99 (1H, m), 4.38 (1H, m), 4.26 (3H, m), 3.89 (2H, m), 3.78 (1H, m), 3.64 (1H, m), 2.74 (1H, m), 2.67 (2H, t), 2.12 (3H, m), 1.74 (1H, m) Primer 223: 4-[2,6-difluoro-4-[2-(tetrahidrofuran-2-ilmetoksi)-3-piridil]fenoksi]buterna kiselina [1440][3755] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.58 (1H, m), 7.11 (2H, m), 6.99 (1H, m), 4.38 (1H, m), 4.26 (3H, m), 3.89 (2H, m), 3.78 (1H, m), 3.64 (1H, m), 2.74 (1H, m), 2.67 (2H, t), 2.12 (3H, m), 1.74 (1H, m) Example 223: 4-[2,6-difluoro-4-[2-(tetrahydrofuran-2-ylmethoxy)-3-pyridyl]phenoxy]butyric acid [1440]

[3757] [3757]

[3760] Faza A: etil 4-[2,6-difluoro-4-[2-(tetrahidrofuran-2-ilmetoksi)-3-piridil] fenoksi]butanoat[3760] Phase A: ethyl 4-[2,6-difluoro-4-[2-(tetrahydrofuran-2-ylmethoxy)-3-pyridyl] phenoxy]butanoate

[3761] 3-jodo-2-(tetrahidrofuran-2-ilmetoksi)piridin (0.12 g, 0.4 mmol) dobijen u primeru pripreme 212 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.18 g, 0.49 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.13 g, 77%).[3761] 3-iodo-2-(tetrahydrofuran-2-ylmethoxy)pyridine (0.12 g, 0.4 mmol) obtained in preparation example 212 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.18 g, 0.49 mmol) obtained in preparation example 2 were used to react in the same manner as in Step A of Example 28 to give the title compound (0.13 g, 77%).

[3762] <1>H-NMR (CDCl<3>) δ 8.31 (1H, m), 7.58 (1H, m), 7.20 (2H, m), 6.96 (1H, m), 4.40 (2H, m), 4.29 (1H, m), 4.21 (2H, t), 4.16 (2H, q), 3.89 (1H, m), 3.79 (1H, m), 2.59 (2H, t), 2.10 (2H, m), 2.01 (1H, m), 1.90 (2H, m), 1.77 (1H, m), 1.27 (3H, t)[3762] <1>H-NMR (CDCl<3>) δ 8.31 (1H, m), 7.58 (1H, m), 7.20 (2H, m), 6.96 (1H, m), 4.40 (2H, m), 4.29 (1H, m), 4.21 (2H, t), 4.16 (2H, q), 3.89 (1H, m), 3.79 (1H, m), 2.59 (2H, t), 2.10 (2H, m), 2.01 (1H, m), 1.90 (2H, m), 1.77 (1H, m), 1.27 (3H, t)

[3764] Faza B: 4-[2,6-difluoro-4-[2-(tetrahidrofuran-2-ilmetoksi)-3-piridil]fenoksi] buterna kiselina [1443] Etil 4-[2,6-difluoro-4-[2-(tetrahidrofuran-2-ilmetoksi)-3-piridil]fenoksi] butanoat (0.13 g, 0.31 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.10 g, 82%).[3764] Phase B: 4-[2,6-difluoro-4-[2-(tetrahydrofuran-2-ylmethoxy)-3-pyridyl]phenoxy] butyric acid [1443] Ethyl 4-[2,6-difluoro-4-[2-(tetrahydrofuran-2-ylmethoxy)-3-pyridyl]phenoxy] butanoate (0.13 g, 0.31 mmol) obtained in phase A was used to react in the same manner. as in Step B of Example 1 to give the title compound (0.10 g, 82%).

[3765] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.58 (1H, m), 7.18 (2H, m), 6.97 (1H, m), 4.42 (1H, m), 4.36 (1H, m), 4.30 (1H, m), 4.24 (2H, t), 3.88 (1H, m), 3.81 (1H, m), 2.66 (2H, t), 2.11 (2H, m), 2.03 (1H, m), 1.90 (2H, m), 1.77 (1H, m)[3765] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.58 (1H, m), 7.18 (2H, m), 6.97 (1H, m), 4.42 (1H, m), 4.36 (1H, m), 4.30 (1H, m), 4.24 (2H, t), 3.88 (1H, m), 3.81 (1H, m), 2.66 (2H, t), 2.11 (2H, m), 2.03 (1H, m), 1.90 (2H, m), 1.77 (1H, m)

[3767] Primer 224: 4-[4-(2-ciklobutilmetoksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina[3767] Example 224: 4-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid

[3768][3768]

[3770] [3770]

[3773] 2-ciklobutilmetoksi-3-jodo-piridin (0.040 g, 0.14 mmol) dobijen u primeru pripreme 61 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.051 g, 0.14 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u primeru 1 da bi se dobilo naslovno jedinjenje (0.025 g, 48 %).[3773] 2-cyclobutylmethoxy-3-iodo-pyridine (0.040 g, 0.14 mmol) obtained in Preparation Example 61 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.051 g, 0.14 mmol) obtained in Preparation Example 2 were used to would react in the same way as in example 1 to obtain the title compound (0.025 g, 48 %).

[3774] 1H NMR (CDCl<3>) δ 8.14 (1H, m), 7.58 (1H, m), 7.16 (2H, m), 6.94 (1H, m), 4.32 (2H, t), 4.24 (2H, t), 2.77 (1H, m), 2.69 (2H, t), 2.13 (4H, m), 1.88 (4H, m)[3774] 1H NMR (CDCl<3>) δ 8.14 (1H, m), 7.58 (1H, m), 7.16 (2H, m), 6.94 (1H, m), 4.32 (2H, t), 4.24 (2H, t), 2.77 (1H, m), 2.69 (2H, t), 2.13 (4H, m), 1.88 (4H, m)

[3776] Primer 225: 4-[4-(2-ciklopropoksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina[3776] Example 225: 4-[4-(2-cyclopropoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid

[3777][3777]

[3779] [3779]

[3782] 2-ciklopropoksi-3-jodo-piridin (0.040 g, 0.14 mmol) dobijen u primeru pripreme 62 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.051 g, 0.14 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u primeru 1 da bi se dobilo naslovno jedinjenje(0.025 g, 52 %).[3782] 2-Cyclopropoxy-3-iodo-pyridine (0.040 g, 0.14 mmol) obtained in Preparation Example 62 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.051 g, 0.14 mmol) obtained in Preparation Example 2 were used to reacted in the same way as in example 1 to obtain the title compound (0.025 g, 52 %).

[3783] 1H NMR (CDCl<3>) δ 8.23 (1H, m), 7.57 (1H, m), 7.07 (2H, m), 6.98 (1H, m), 4.35 (1H, m), 4.24 (2H, t), 2.68 (2H, t), 2.12 (2H, m), 0.82 (4H, m)[3783] 1H NMR (CDCl<3>) δ 8.23 (1H, m), 7.57 (1H, m), 7.07 (2H, m), 6.98 (1H, m), 4.35 (1H, m), 4.24 (2H, t), 2.68 (2H, t), 2.12 (2H, m), 0.82 (4H, m)

[3785] Primer 226: 4-(4-{2-[3-(tert-butil-dimetil-silaniloksi)-ciklopentiloksi]-piridin-3-il}-2,6-diflu oro-fenoksi)-buterna kiselina[3785] Example 226: 4-(4-{2-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyloxy]-pyridin-3-yl}-2,6-difluoro-phenoxy)-butyric acid

[3786][3786]

[3788] [3788]

[3791] Faza A: etil estar 4-(4-{2-[3-(tert-butil-dimetil-silaniloksi)-ciklopentiloksi]-piridin-3-il}-2,6-difluorofenoksi)-buterne kiseline[3791] Phase A: 4-(4-{2-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyloxy]-pyridin-3-yl}-2,6-difluorophenoxy)-butyric acid ethyl ester

[3792] 2-[3-(tert-butil-dimetil-silaniloksi)-ciklopentiloksil-3-jodo-piridin (0.10 g, 0.24 mmol) dobijen u primeru pripreme 213 i etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]buterne kiseline (0.088 g, 0.24 mmol) dobijen u primeru pripreme 2 su korišćeni da bi reagovali na isti način kao u fazi A primera 1 da bi se dobilo naslovno jedinjenje (0.12 g, 94 %).[3792] 2-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyloxyl-3-iodo-pyridine (0.10 g, 0.24 mmol) obtained in Preparation Example 213 and 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]butyric acid ethyl ester (0.088 g, 0.24 mmol) obtained in Preparative Example 2 were used to react in the same manner as in Step A of Example 1 to give the title compound (0.12 g, 94 %).

[3794] Faza B: 4-(4-{2-[3-(tert-butil-dimetil-silaniloksi)-ciklopentiloksi]-piridin-3-il}-2,6-difluoro-fenoksi)-buterna kiselina[3794] Phase B: 4-(4-{2-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyloxy]-pyridin-3-yl}-2,6-difluoro-phenoxy)-butyric acid

[3795] Etil estar 4-(4-{2-[3-(tert-butil-dimetil-silaniloksi)-ciklopentiloksi]-piridin-3-il}-2,6-difluorofenoksi)-buterne kiseline (20 mg, 0.04 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (15 mg, 79 %).[3795] 4-(4-{2-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyloxy]-pyridin-3-yl}-2,6-difluorophenoxy)-butyric acid ethyl ester (20 mg, 0.04 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (15 mg, 79%).

[3796] 1H NMR (CDCl<3>) δ 8.14 (1H, m), 7.54 (1H, m), 7.13 (2H, m), 6.92 (1H, m), 5.59 (1H, m), 4.41 (1H, m), 4.24 (2H, t), 2.69 (2H, t), 2.28 (1H, m), 2.13 (2H, m), 2.03 (3H, m), 1.75 (1H, m), 1.61 (1H, m), 0.91 (9H, s), 0.08 (6H, s)[3796] 1H NMR (CDCl<3>) δ 8.14 (1H, m), 7.54 (1H, m), 7.13 (2H, m), 6.92 (1H, m), 5.59 (1H, m), 4.41 (1H, m), 4.24 (2H, t), 2.69 (2H, t), 2.28 (1H, m), 2.13 (2H, m), 2.03 (3H, m), 1.75 (1H, m), 1.61 (1H, m), 0.91 (9H, s), 0.08 (6H, s)

[3798] Primer 227: 4-{2,6-difluoro-4-[2-(3-hidroksi-ciklopentiloksi)-piridin-3-il]-fenoksi}-buterna kiselina [1455][3798] Example 227: 4-{2,6-difluoro-4-[2-(3-hydroxy-cyclopentyloxy)-pyridin-3-yl]-phenoxy}-butyric acid [1455]

[3800] [3800]

[3803] Faza A: etil estar 4-{2,6-difluoro-4-[2-(3-hidroksi-ciklopentiloksi)-piridin-3-il]-fenoksi}-buterne kiseline [1456] Etil estar 4-(4-{2-[3-(tert-butil-dimetil-silaniloksi)-ciklopentiloksi]-piridin-3-il}-2,6-difluorofenoksi)-buterne kiseline (0.10 g, 0.19 mmol) dobijen u fazi A primera 226 je rastvoren u 1 mL tetrahidrofurana. Dodat je TBAF (0.28 mL, 0.28 mmol, 1.0 M u THF-u), i proizvod je mešan 3 sata na sobnoj temperaturi. Ekstrakcija je izvedena sa vodom i etilacetatom, i proizvod je opran fiziološkim rastvorom. Proizvod je osušen sa MgSO<4>, koncentrovan i prečišćena hromatografijom na koloni da bi se dobilo naslovno jedinjenje (60 mg, 76 %).[3803] Phase A: 4-{2,6-difluoro-4-[2-(3-hydroxy-cyclopentyloxy)-pyridin-3-yl]-phenoxy}-butyric acid ethyl ester [1456] 4-{4-{2-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyloxy]-pyridin-3-yl}-2,6-difluorophenoxy)-butyric acid (0.10 g, 0.19 mmol) obtained in phase A of Example 226 was dissolved in 1 mL of tetrahydrofuran. TBAF (0.28 mL, 0.28 mmol, 1.0 M in THF) was added, and the product was stirred for 3 h at room temperature. Extraction was performed with water and ethyl acetate, and the product was washed with saline. The product was dried with MgSO<4> , concentrated and purified by column chromatography to give the title compound (60 mg, 76 %).

[3805] Faza B: 4-{2,6-difluoro-4-[2-(3-hidroksi-ciklopentiloksi)-piridin-3-il]-fenoksi}-buterna kiselina [1457] Etil estar 4-{2,6-difluoro-4-[2-(3-hidroksi-ciklopentiloksi)-piridin-3-il]-fenoksi}-buterne kiseline (55 mg, 0.13 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (45 mg, 88 %).[3805] Phase B: 4-{2,6-difluoro-4-[2-(3-hydroxy-cyclopentyloxy)-pyridin-3-yl]-phenoxy}-butyric acid [1457] 4-{2,6-difluoro-4-[2-(3-hydroxy-cyclopentyloxy)-pyridin-3-yl]-phenoxy}-butyric acid ethyl ester (55 mg, 0.13 mmol) obtained in phase A was used to reacted in the same manner as in Step B of Example 1 to give the title compound (45 mg, 88%).

[3806] 1H NMR (CDCl<3>) δ 8.15 (1H, m), 7.55 (1H, m), 7.11 (2H, m), 6.94 (1H, m), 5.64 (1H, m), 4.50 (1H, m), 4.25 (2H, t), 2.68 (2H, t), 2.28 (1H, m), 2.13 (5H, m), 1.83 (1H, m), 1.66 (1H, m)[3806] 1H NMR (CDCl<3>) δ 8.15 (1H, m), 7.55 (1H, m), 7.11 (2H, m), 6.94 (1H, m), 5.64 (1H, m), 4.50 (1H, m), 4.25 (2H, t), 2.68 (2H, t), 2.28 (1H, m), 2.13 (5H, m), 1.83 (1H, m), 1.66 (1H, m)

[3808] Primer 228: 4-[4-(2-cikloheksiloksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina[3808] Example 228: 4-[4-(2-cyclohexyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid

[3809][3809]

[3811] [3811]

[3813] Cikloheksanol (45 mg, 0.45 mmol) i 4-[2,6-difluoro-4-(2-fluoro-3-piridil)fenoksi]buterna kiselina (70 mg, 0.22 mmol) dobijen u primeru pripreme 56 su korišćeni da bi reagovali na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (40 mg, 45 %).[3813] Cyclohexanol (45 mg, 0.45 mmol) and 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butyric acid (70 mg, 0.22 mmol) obtained in Preparative Example 56 were used to react in the same manner as in Preparative Example 37 to give the title compound (40 mg, 45%).

[3814] 1H NMR (CDCl<3>) δ 8.13 (1H, m), 7.56 (1H, m), 7.18 (2H, m), 6.92 (1H, m), 5.18 (1H, m), 4.24 (2H, t), 2.69 (2H, t), 2.13 (2H, m), 1.96 (2H, m), 1.70 (2H, m), 1.58 (3H, m), 1.45 (2H, m), 1.35 (1H, m)[3814] 1H NMR (CDCl<3>) δ 8.13 (1H, m), 7.56 (1H, m), 7.18 (2H, m), 6.92 (1H, m), 5.18 (1H, m), 4.24 (2H, t), 2.69 (2H, t), 2.13 (2H, m), 1.96 (2H, m), 1.70 (2H, m), 1.58 (3H, m), 1.45 (2H, m), 1.35 (1H, m)

[3816] Primer 229: 4-[4-(2-ciklopentilmetoksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina[3816] Example 229: 4-[4-(2-cyclopentylmethoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid

[3817][3817]

[3819] [3819]

[3822] Ciklopentil-metanol (45 mg, 0.45 mmol) i 4-[2,6-difluoro-4-(2-fluoro-3-piridil)fenoksi]buterna kiselina (70 mg, 0.22 mmol) dobijena u primeru pripreme 56 su korišćeni da bi reagovali na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (55 mg, 62 %).[3822] Cyclopentyl methanol (45 mg, 0.45 mmol) and 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butyric acid (70 mg, 0.22 mmol) obtained in Preparative Example 56 were used to react in the same manner as in Preparative Example 37 to give the title compound (55 mg, 62%).

[3823] 1H NMR (CDCl<3>) δ 8.14 (1H, m), 7.57 (1H, m), 7.18 (2H, m), 6.95 (1H, m), 4.24 (4H, m), 2.69 (2H, t), 2.37 (1H, m), 2.13 (2H, m), 1.80 (2H, m), 1.62 (4H, m), 1.36 (2H, m)[3823] 1H NMR (CDCl<3>) δ 8.14 (1H, m), 7.57 (1H, m), 7.18 (2H, m), 6.95 (1H, m), 4.24 (4H, m), 2.69 (2H, t), 2.37 (1H, m), 2.13 (2H, m), 1.80 (2H, m), 1.62 (4H, m), 1.36 (2H, m)

[3825] Primer 230: 4-[2,6-difluoro-4-(2-isobutoksi-piridin-3-il)-fenoksi]-buterna kiselina[3825] Example 230: 4-[2,6-difluoro-4-(2-isobutoxy-pyridin-3-yl)-phenoxy]-butyric acid

[3826][3826]

[3828] [3828]

[3831] 2-metil-propan-1-ol (33 mg, 0.45 mmol) i 4-[2,6-difluoro-4-(2-fluoro-3-piridil)fenoksi]buterna kiselina (70 mg, 0.22 mmol) dobijena u primeru pripreme 56 su korišćeni da bi reagovali na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (50 mg, 61 %).[3831] 2-Methyl-propan-1-ol (33 mg, 0.45 mmol) and 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butyric acid (70 mg, 0.22 mmol) obtained in Preparative Example 56 were used to react in the same manner as in Preparative Example 37 to give the title compound (50 mg, 61%).

[3832] 1H NMR (CDCl<3>) δ 8.14 (1H, m), 7.58 (1H, m), 7.17 (2H, m), 6.95 (1H, m), 4.25 (2H, t), 4.13 (2H, d), 2.69 (2H, t), 2.13 (3H, m), 1.00 (6H, d)[3832] 1H NMR (CDCl<3>) δ 8.14 (1H, m), 7.58 (1H, m), 7.17 (2H, m), 6.95 (1H, m), 4.25 (2H, t), 4.13 (2H, d), 2.69 (2H, t), 2.13 (3H, m), 1.00 (6H, d)

[3834] Primer 231: 4-{4-[2-(2,2-dimeti-propoksi)-piridin-3-il]-2,6-difluoro-fenoksil-buterna kiselina [1468][3834] Example 231: 4-{4-[2-(2,2-dimethyl-propoxy)-pyridin-3-yl]-2,6-difluoro-phenoxyl-butyric acid [1468]

[3836] [3836]

[3837] 2,2-dimetil-propan-1-ol (40 mg, 0.45 mmol) i 4-[2,6-difluoro-4-(2-fluoro-3-piridil)fenoksi]buterna kiselina (70 mg, 0.22 mmol) dobijena u primeru pripreme 56 su korišćeni da bi reagovali na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (40 mg, 47 %).[3837] 2,2-dimethyl-propan-1-ol (40 mg, 0.45 mmol) and 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butyric acid (70 mg, 0.22 mmol) obtained in Preparative Example 56 were used to react in the same manner as in Preparative Example 37 to give the title compound (40 mg, 47%).

[3838] 1H NMR (CDCl<3>) δ 8.15 (1H, m), 7.58 (1H, m), 7.18 (2H, m), 6.95 (1H, m), 4.25 (2H, t), 4.02 (2H, s), 2.69 (2H, t), 2.13 (2H, m), 0.98 (9H, s)[3838] 1H NMR (CDCl<3>) δ 8.15 (1H, m), 7.58 (1H, m), 7.18 (2H, m), 6.95 (1H, m), 4.25 (2H, t), 4.02 (2H, s), 2.69 (2H, t), 2.13 (2H, m), 0.98 (9H, s)

[3840] Primer 232: 5-[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenoksi]-valerijanska kiselina[3840] Example 232: 5-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-valeric acid

[3841][3841]

[3843] [3843]

[3846] Faza A: etil estar 5-[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenoksi]-valerijanske kiseline [1472] Etil estar 5-bromo-valerijanska kiselina (43 mg, 0.21 mmol) i 4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenol (50 mg, 0.17 mmol) dobijen u primeru pripreme 55 su korišćeni da bi reagovali na isti način kao u fazi C primera pripreme 2 da bi se dobilo naslovno jedinjenje (50 mg, 69 %).[3846] Phase A: 5-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-valeric acid ethyl ester [1472] 5-Bromo-valeric acid ethyl ester (43 mg, 0.21 mmol) and 4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenol (50 mg, 0.17 mmol) were obtained. in Preparative Example 55 were used to react in the same manner as in Step C of Preparative Example 2 to give the title compound (50 mg, 69%).

[3848] Faza B: 5-[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenoksi]-valerijanska kiselina[3848] Phase B: 5-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-valeric acid

[3849] Etil estar 5-[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenoksi]-valerijanske kiseline (45 mg, 0.11 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (36 mg, 86 %).[3849] 5-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-valeric acid ethyl ester (45 mg, 0.11 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (36 mg, 86%).

[3850] 1H NMR (CDCl<3>) δ 8.15 (1H, m), 7.56 (1H, m), 7.15 (2H, m), 6.92 (1H, m), 5.51 (1H, m), 4.19 (2H, t), 2.47 (2H, t), 2.00∼1.70 (10H, m), 1.64 (2H, m)[3850] 1H NMR (CDCl<3>) δ 8.15 (1H, m), 7.56 (1H, m), 7.15 (2H, m), 6.92 (1H, m), 5.51 (1H, m), 4.19 (2H, t), 2.47 (2H, t), 2.00∼1.70 (10H, m), 1.64 (2H, m)

[3852] Primer 233: 5-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]valerijanska kiselina[3852] Example 233: 5-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]valeric acid

[3853][3853]

[3855] [3855]

[3858] Faza A: etil 5-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksil] pentanoat[3858] Phase A: ethyl 5-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxyl] pentanoate

[3859] 2-ciklobutilsulfanil-3-jodo-piridin (0.064 g, 0.22 mmol) dobijen u primeru pripreme 44 i etil 5-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]pentanoat (0.095 g, 0.247 mmol) dobijen u primeru pripreme 225 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.07 g, 75%).[3859] 2-cyclobutylsulfanyl-3-iodo-pyridine (0.064 g, 0.22 mmol) obtained in preparation example 44 and ethyl 5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pentanoate (0.095 g, 0.247 mmol) obtained in preparation example 225 were used to react in the same manner as in Step A of Example 28 to give the title compound (0.07 g, 75%).

[3860] <1>H-NMR (CDCl<3>) δ 8.40 (1H, m), 7.32 (1H, m), 7.02 (1H, m), 6.98 (2H, m), 4.42 (1H, m), 4.21 (2H, t), 4.15 (2H, q), 2.51 (2H, m), 2.41 (2H, t), 2.04 (4H, m), 1.86 (4H, m), 1.27 (3H, t)[3860] <1>H-NMR (CDCl<3>) δ 8.40 (1H, m), 7.32 (1H, m), 7.02 (1H, m), 6.98 (2H, m), 4.42 (1H, m), 4.21 (2H, t), 4.15 (2H, q), 2.51 (2H, m), 2.41 (2H, t), 2.04 (4H, m), 1.86 (4H, m), 1.27 (3H, t)

[3862] Faza B: 5-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]valerijanska kiselina[3862] Phase B: 5-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]valeric acid

[3863] Etil 5-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]pentanoat (0.07 g, 0.16 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.065 g, 99%).[3863] Ethyl 5-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]pentanoate (0.07 g, 0.16 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.065 g, 99%).

[3864] <1>H-NMR (CDCl<3>) δ 8.41 (1H, m), 7.31 (1H, m), 7.03 (1H, m), 6.97 (2H, m), 4.43 (1H, m), 4.21 (2H, t), 2.52 (4H, m), 2.10 (4H, m), 1.90 (4H, m)[3864] <1>H-NMR (CDCl<3>) δ 8.41 (1H, m), 7.31 (1H, m), 7.03 (1H, m), 6.97 (2H, m), 4.43 (1H, m), 4.21 (2H, t), 2.52 (4H, m), 2.10 (4H, m), 1.90 (4H, m)

[3866] Primer 234: 5-[4-(2-ciklopentilsulfanil-3-piridil)-2,6-difluoro-fenoksi] valerijanska kiselina[3866] Example 234: 5-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy] valeric acid

[3867][3867]

[3869] [3869]

[3872] Faza A: etil 5-[4-(2-ciklopentilsulfanil-3-piridil)-2,6-difluoro-fenoksi] pentanoat[3872] Phase A: ethyl 5-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy] pentanoate

[3873] 2-ciklopentilsulfanil-3-jodo-piridin (0.067 g, 0.22 mmol) dobijen u primeru pripreme 39 i etil 5-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksilpentanoat (0.095 g, 0.25 mmol) dobijen u primeru pripreme 225 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.057 g, 59%).[3873] 2-cyclopentylsulfanyl-3-iodo-pyridine (0.067 g, 0.22 mmol) obtained in Preparation Example 39 and ethyl 5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxylpentanoate (0.095 g, 0.25 mmol) obtained in Preparation Example 225 were used to react in the same manner as in Step A of Example 28 to give the title compound (0.057 g, 59%).

[3874] <1>H-NMR (CDCl<3>) δ 8.43 (1H, m), 7.32 (1H, m), 7.02 (1H, m), 6.98 (2H, m), 4.20 (2H, t), 4.16 (2H, q), 4.11 (1H, m), 2.40 (2H, t), 2.20 (2H, m), 1.86 (4H, m), 1.73 (2H, m), 1.62 (4H, m), 1.27 (3H, t)[3874] <1>H-NMR (CDCl<3>) δ 8.43 (1H, m), 7.32 (1H, m), 7.02 (1H, m), 6.98 (2H, m), 4.20 (2H, t), 4.16 (2H, q), 4.11 (1H, m), 2.40 (2H, t), 2.20 (2H, m), 1.86 (4H, m), 1.73 (2H, m), 1.62 (4H, m), 1.27 (3H, t)

[3876] Faza B: 5-[4-(2-ciklopentilsulfanil-3-piridil)-2,6-difluoro-fenoksi]valerijanska kiselina[3876] Phase B: 5-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]valeric acid

[3877] Etil 5-[4-(2-ciklopentilsulfanil-3-piridil)-2,6-difluoro-fenoksi]pentanoat (0.057 g, 0.13 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.051 g, 97%).[3877] Ethyl 5-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]pentanoate (0.057 g, 0.13 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.051 g, 97%).

[3878] <1>H-NMR (CDCl<3>) δ 8.43 (1H, m), 7.31 (1H, m), 7.03 (1H, m), 6.97 (2H, m), 4.21 (2H, t), 4.10 (1H, m), 2.48 (2H, t), 2.20 (2H, m), 1.89 (4H, m), 1.72 (2H, m), 1.60 (4H, m)[3878] <1>H-NMR (CDCl<3>) δ 8.43 (1H, m), 7.31 (1H, m), 7.03 (1H, m), 6.97 (2H, m), 4.21 (2H, t), 4.10 (1H, m), 2.48 (2H, t), 2.20 (2H, m), 1.89 (4H, m), 1.72 (2H, m), 1.60 (4H, m)

[3879] Primer 235: 5-[2,6-difluoro-4-(2-izopropilsulfanil-3-piridil)fenoksi] valerijanska kiselina[3879] Example 235: 5-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenoxy]valeric acid

[3880][3880]

[3882] [3882]

[3885] Faza A: etil 5-[2,6-difluoro-4-(2-izopropilsulfanil-3-piridil)fenoksi]pentanoat[3885] Phase A: ethyl 5-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenoxy]pentanoate

[3886] 3-jodo-2-izopropilsulfanil-piridin (0.062 g, 0.22 mmol) dobijen u primeru pripreme 226 i etil 5-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksilpentanoat (0.095 g, 0.25 mmol) dobijen u primeru pripreme 225 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.063 g, 70%).[3886] 3-Iodo-2-isopropylsulfanyl-pyridine (0.062 g, 0.22 mmol) obtained in Preparation Example 226 and ethyl 5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxylpentanoate (0.095 g, 0.25 mmol) obtained in Preparation Example 225 were used to react in the same manner as in Step A of Example 28 to give the title compound (0.063 g, 70%).

[3887] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.33 (1H, m), 7.03 (1H, m), 6.97 (2H, m), 4.20 (2H, t), 4.15 (2H, q), 4.07 (1H, m), 2.41 (2H, t), 1.87 (4H, m), 1.37 (6H, d), 1.27 (3H, t)[3887] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.33 (1H, m), 7.03 (1H, m), 6.97 (2H, m), 4.20 (2H, t), 4.15 (2H, q), 4.07 (1H, m), 2.41 (2H, t), 1.87 (4H, m), 1.37 (6H, d), 1.27 (3H, t)

[3889] Faza B: 5-[2,6-difluoro-4-(2-izopropilsulfanil-3-piridil)fenoksi]valerijanska kiselina[3889] Phase B: 5-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenoxy]valeric acid

[3890] Etil 5-[2,6-difluoro-4-(2-izopropilsulfanil-3-piridil)fenoksi]pentanoat (0.063 g, 0.155 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.058 g, 98%).[3890] Ethyl 5-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenoxy]pentanoate (0.063 g, 0.155 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.058 g, 98%).

[3891] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.34 (1H, m), 7.02 (1H, m), 6.96 (2H, m), 4.21 (2H, t), 4.06 (1H, m), 2.48 (2H, t), 1.89 (4H, m), 1.36 (6H, d)[3891] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.34 (1H, m), 7.02 (1H, m), 6.96 (2H, m), 4.21 (2H, t), 4.06 (1H, m), 2.48 (2H, t), 1.89 (4H, m), 1.36 (6H, d)

[3893] Primer 236: 5-[2,6-difluoro-4-(2-propilsulfanil-3-piridil)fenoksi] valerijanska kiselina[3893] Example 236: 5-[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)phenoxy] valeric acid

[3894][3894]

[3896] [3896]

[3899] Faza A: etil 5-[2,6-difluoro-4-(2-propilsulfanil-3-piridil)fenoksi]pentanoat[3899] Phase A: ethyl 5-[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)phenoxy]pentanoate

[3900] 3-jodo-2-propilsulfanil-piridin (0.062 g, 0.22 mmol) dobijen u primeru pripreme 203 i etil 5-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksilpentanoat (0.095 g, 0.25 mmol) dobijen u primeru pripreme 225 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.04 g, 44%).[3900] 3-iodo-2-propylsulfanyl-pyridine (0.062 g, 0.22 mmol) obtained in preparation example 203 and ethyl 5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxylpentanoate (0.095 g, 0.25 mmol) obtained in preparation example 225 were used to react in the same manner as in Step A of Example 28 to give the title compound (0.04 g, 44%).

[3901] <1>H-NMR (CDCl<3>) δ 8.43 (1H, m), 7.33 (1H, m), 7.03 (1H, m), 6.99 (2H, m), 4.20 (2H, t), 4.14 (2H, q), 3.15 (2H, t), 2.39 (2H, t), 1.86 (4H, m), 1.69 (2H, m), 1.27 (3H, t), 1.02 (3H, t)[3901] <1>H-NMR (CDCl<3>) δ 8.43 (1H, m), 7.33 (1H, m), 7.03 (1H, m), 6.99 (2H, m), 4.20 (2H, t), 4.14 (2H, q), 3.15 (2H, t), 2.39 (2H, t), 1.86 (4H, m), 1.69 (2H, m), 1.27 (3H, t), 1.02 (3H, t)

[3902] Faza B: 5-[2,6-difluoro-4-(2-propilsulfanil-3-piridil)fenoksi]valerijanska kiselina[3902] Phase B: 5-[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)phenoxy]valeric acid

[3903] Etil 5-[2,6-difluoro-4-(2-propilsulfanil-3-piridil)fenoksi]pentanoat (0.04 g, 0.1 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.022 g, 58%).[3903] Ethyl 5-[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)phenoxy]pentanoate (0.04 g, 0.1 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.022 g, 58%).

[3904] <1>H-NMR (CDCl<3>) δ 8.43 (1H, m), 7.34 (1H, m), 7.03 (1H, m), 6.99 (2H, m), 4.2 (2H, t), 3.14 (2H, t), 2.49 (2H, t), 1.89 (4H, m), 1.67 (2H, m), 1.02 (3H, t)[3904] <1>H-NMR (CDCl<3>) δ 8.43 (1H, m), 7.34 (1H, m), 7.03 (1H, m), 6.99 (2H, m), 4.2 (2H, t), 3.14 (2H, t), 2.49 (2H, t), 1.89 (4H, m), 1.67 (2H, m), 1.02 (3H, t)

[3906] Primer 237: 5-[2,6-difluoro-4-(6-izopropilsulfanil-2-piridil)fenoksi] valerijanska kiselina[3906] Example 237: 5-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]valeric acid

[3907][3907]

[3909] [3909]

[3912] Faza A: etil 5-[2,6-difluoro-4-(6-izopropilsulfanil-2-piridil)fenoksil pentanoat[3912] Phase A: ethyl 5-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenoxyl pentanoate

[3913] 2-hloro-6-izopropilsulfanil-piridin (0.05 g, 0.26 mmol) dobijen u primeru pripreme 125 i etil 5-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksilpentanoat (0.098 g, 0.25 mmol) dobijen u primeru pripreme 225 su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.068 g, 65%).[3913] 2-chloro-6-isopropylsulfanyl-pyridine (0.05 g, 0.26 mmol) obtained in preparation example 125 and ethyl 5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxylpentanoate (0.098 g, 0.25 mmol) obtained in preparation example 225 were used to react in the same manner as in Step A of Example 29 to give the title compound (0.068 g, 65%).

[3914] <1>H-NMR (CDCl<3>) δ 7.58 (2H, m), 7.52 (1H, t), 7.31 (1H, d), 7.08 (1H, d), 4.20 (2H, t), 4.14 (3H, m), 2.40 (2H, t), 1.85 (4H, m), 1.47 (6H, d), 1.26 (3H, t)[3914] <1>H-NMR (CDCl<3>) δ 7.58 (2H, m), 7.52 (1H, t), 7.31 (1H, d), 7.08 (1H, d), 4.20 (2H, t), 4.14 (3H, m), 2.40 (2H, t), 1.85 (4H, m), 1.47 (6H, d), 1.26 (3H, t)

[3916] Faza B: 5-[2,6-difluoro-4-(6-izopropilsulfanil-2-piridil)fenoksi]valerijanska kiselina[3916] Phase B: 5-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]valeric acid

[3917] Etil 5-[2,6-difluoro-4-(6-izopropilsulfanil-2-piridil)fenoksi]pentanoat (0.068 g, 0.16 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.046 g, 73%).[3917] Ethyl 5-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]pentanoate (0.068 g, 0.16 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.046 g, 73%).

[3918] <1>H-NMR (CDCl<3>) δ 7.59 (2H, m), 7.52 (1H, t), 7.31 (1H, d), 7.08 (1H, d), 4.22 (2H, t), 4.14 (1H, m), 2.47 (2H, t), 1.87 (4H, m), 1.48 (6H, d)[3918] <1>H-NMR (CDCl<3>) δ 7.59 (2H, m), 7.52 (1H, t), 7.31 (1H, d), 7.08 (1H, d), 4.22 (2H, t), 4.14 (1H, m), 2.47 (2H, t), 1.87 (4H, m), 1.48 (6H, d)

[3920] Primer 238: 5-[2,6-difluoro-4-(6-izopropoksi-2-piridil)fenoksi]valerijanska kiselina[3920] Example 238: 5-[2,6-difluoro-4-(6-isopropoxy-2-pyridyl)phenoxy]valeric acid

[3921][3921]

[3923] [3923]

[3924] Faza A: etil 5-[2,6-difluoro-4-(6-izopropoksi-2-piridil)fenoksi]pentanoat[3924] Phase A: ethyl 5-[2,6-difluoro-4-(6-isopropoxy-2-pyridyl)phenoxy]pentanoate

[3925] 2-hloro-6-izopropoksi-piridin (0.039 g, 0.22 mmol) dobijen u primeru pripreme 21 i etil 5-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksilpentanoat (0.098 g, 0.25 mmol) dobijen u primeru pripreme 225 su korišćeni da bi reagovali na isti način kao u fazi A primera 29 da bi se dobilo naslovno jedinjenje (0.079 g, 89%).[3925] 2-Chloro-6-isopropoxy-pyridine (0.039 g, 0.22 mmol) obtained in Preparation Example 21 and ethyl 5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxylpentanoate (0.098 g, 0.25 mmol) obtained in Preparation Example 225 were used to would react in the same manner as in step A of Example 29 to give the title compound (0.079 g, 89%).

[3926] <1>H-NMR (CDCl<3>) δ 7.57 (3H, m), 7.19 (1H, d), 6.63 (1H, d), 5.45 (1H, m), 4.19 (2H, t), 4.14 (2H, q), 2.40 (2H, t), 1.85 (4H, m), 1.40 (6H, d), 1.27 (3H, t)[3926] <1>H-NMR (CDCl<3>) δ 7.57 (3H, m), 7.19 (1H, d), 6.63 (1H, d), 5.45 (1H, m), 4.19 (2H, t), 4.14 (2H, q), 2.40 (2H, t), 1.85 (4H, m), 1.40 (6H, d), 1.27 (3H, t)

[3928] Faza B: 5-[2,6-difluoro-4-(6-izopropoksi-2-piridil)fenoksi]valerijanska kiselina[3928] Phase B: 5-[2,6-difluoro-4-(6-isopropoxy-2-pyridyl)phenoxy]valeric acid

[3929] Etil 5-[2,6-difluoro-4-(6-izopropoksi-2-piridil)fenoksi]pentanoat (0.079 g, 0.2 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.070 g, 96%).[3929] Ethyl 5-[2,6-difluoro-4-(6-isopropoxy-2-pyridyl)phenoxy]pentanoate (0.079 g, 0.2 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.070 g, 96%).

[3930] <1>H-NMR (CDCl<3>) δ 7.58 (3H, m), 7.19 (1H, d), 6.63 (1H, d), 5.44 (1H, m), 4.20 (2H, t), 2.47 (2H, t), 1.87 (4H, m), 1.40 (6H, d)[3930] <1>H-NMR (CDCl<3>) δ 7.58 (3H, m), 7.19 (1H, d), 6.63 (1H, d), 5.44 (1H, m), 4.20 (2H, t), 2.47 (2H, t), 1.87 (4H, m), 1.40 (6H, d)

[3932] Primer 239: 5-[4-[2-(ciklopropilmetoksi)-3-piridil]-2,6-difluoro-fenoksi]valerijanska kiselina [1505][3932] Example 239: 5-[4-[2-(cyclopropylmethoxy)-3-pyridyl]-2,6-difluoro-phenoxy]valeric acid [1505]

[3934] [3934]

[3937] Faza A: etil 5-[4-[2-(ciklopropilmetoksi)-3-piridil]-2,6-difluoro-fenoksi] pentanoat[3937] Phase A: ethyl 5-[4-[2-(cyclopropylmethoxy)-3-pyridyl]-2,6-difluoro-phenoxy] pentanoate

[3938] 2-ciklopropilmetoksi-3-jodo-piridin (0.062 g, 0.22 mmol) dobijen u primeru pripreme 40 i etil 5-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksilpentanoat (0.095 g, 0.25 mmol) dobijen u primeru pripreme 225 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.072 g, 79%).[3938] 2-cyclopropylmethoxy-3-iodo-pyridine (0.062 g, 0.22 mmol) obtained in Preparation Example 40 and ethyl 5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxylpentanoate (0.095 g, 0.25 mmol) obtained in Preparation Example 225 were used. to react in the same manner as in Step A of Example 28 to give the title compound (0.072 g, 79%).

[3939] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.58 (1H, m), 7.22 (2H, m), 6.95 (1H, m), 4.22 (2H, d), 4.19 (2H, t), 4.14 (2H, q), 2.40 (2H, t), 1.85 (4H, m), 1.26 (4H, m), 0.60 (2H, m), 0.35 (2H, m)[3939] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.58 (1H, m), 7.22 (2H, m), 6.95 (1H, m), 4.22 (2H, d), 4.19 (2H, t), 4.14 (2H, q), 2.40 (2H, t), 1.85 (4H, m), 1.26 (4H, m), 0.60 (2H, m), 0.35 (2H, m)

[3941] Faza B: 5-[4-[2-(ciklopropilmetoksi)-3-piridil]-2,6-difluoro-fenoksi]valerijanska kiselina[3941] Phase B: 5-[4-[2-(cyclopropylmethoxy)-3-pyridyl]-2,6-difluoro-phenoxy]valeric acid

[3942] Etil 5-[4-[2-(ciklopropilmetoksi)-3-piridil]-2,6-difluoro-fenoksi]pentanoat (0.072 g, 0.18 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.067 g, 99%).[3942] Ethyl 5-[4-[2-(cyclopropylmethoxy)-3-pyridyl]-2,6-difluoro-phenoxy]pentanoate (0.072 g, 0.18 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.067 g, 99%).

[3943] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.58 (1H, m), 7.21 (2H, m), 6.94 (1H, m), 4.21 (4H, m), 2.48 (2H, t), 1.88 (4H, m), 1.30 (1H, m), 0.60 (2H, m), 0.34 (2H, m)[3943] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.58 (1H, m), 7.21 (2H, m), 6.94 (1H, m), 4.21 (4H, m), 2.48 (2H, t), 1.88 (4H, m), 1.30 (1H, m), 0.60 (2H, m), 0.34 (2H, m)

[3944] Primer 240: 5-[2,6-difluoro-4-(2-tetrahidrofuran-3-iloksi-3-piridil) fenoksi]valerijanska kiselina [1510][3944] Example 240: 5-[2,6-difluoro-4-(2-tetrahydrofuran-3-yloxy-3-pyridyl)phenoxy]valeric acid [1510]

[3946] [3946]

[3949] Faza A: etil 5-[2,6-difluoro-4-(2-tetrahidrofuran-3-iloksi-3-piridil)fenoksi] pentanoat[3949] Phase A: ethyl 5-[2,6-difluoro-4-(2-tetrahydrofuran-3-yloxy-3-pyridyl)phenoxy] pentanoate

[3950] 3-jodo-2-(tetrahidrofuran-3-iloksi)-piridin(0.066 g, 0.22 mmol) dobijen u primeru pripreme 59 i etil 5-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]pentanoat (0.095 g, 0.25 mmol) dobijen u primeru pripreme 225 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.06 g, 63%).[3950] 3-iodo-2-(tetrahydrofuran-3-yloxy)-pyridine (0.066 g, 0.22 mmol) obtained in preparation example 59 and ethyl 5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pentanoate (0.095 g, 0.25 mmol) obtained in preparation example 59 225 were used to react in the same manner as in Step A of Example 28 to give the title compound (0.06 g, 63%).

[3951] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.58 (1H, m), 7.14 (2H, m), 6.97 (1H, m), 5.63 (1H, m), 4.19 (2H, t), 4.14 (2H, q), 4.10 (1H, m), 3.93 (3H, m), 2.40 (2H, t), 2.25 (1H, m), 2.15 (1H, m), 1.85 (4H, m), 1.26 (3H, t)[3951] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.58 (1H, m), 7.14 (2H, m), 6.97 (1H, m), 5.63 (1H, m), 4.19 (2H, t), 4.14 (2H, q), 4.10 (1H, m), 3.93 (3H, m), 2.40 (2H, t), 2.25 (1H, m), 2.15 (1H, m), 1.85 (4H, m), 1.26 (3H, t)

[3953] Faza B: 5-[2,6-difluoro-4-(2-tetrahidrofuran-3-iloksi-3-piridil)fenoksi]valerijanska kiselina[3953] Phase B: 5-[2,6-difluoro-4-(2-tetrahydrofuran-3-yloxy-3-pyridyl)phenoxy]valeric acid

[3954] Etil 5-[2,6-difluoro-4-(2-tetrahidrofuran-3-iloksi-3-piridil)fenoksi] pentanoat (0.06 g, 0.14 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.055 g, 99%).[3954] Ethyl 5-[2,6-difluoro-4-(2-tetrahydrofuran-3-yloxy-3-pyridyl)phenoxy] pentanoate (0.06 g, 0.14 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.055 g, 99%).

[3955] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.58 (1H, m), 7.12 (2H, m), 6.98 (1H, m), 5.65 (1H, m), 4.21 (2H, t), 4.07 (1H, m), 3.93 (3H, m), 2.46 (2H, t), 2.25 (1H, m), 2.15 (1H, m), 1.86 (4H, m)[3955] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.58 (1H, m), 7.12 (2H, m), 6.98 (1H, m), 5.65 (1H, m), 4.21 (2H, t), 4.07 (1H, m), 3.93 (3H, m), 2.46 (2H, t), 2.25 (1H, m), 2.15 (1H, m), 1.86 (4H, m)

[3957] Primer 241: 5-[2,6-difluoro-4-(2-tetrahidropiran-4-iloksi-3-piridil) fenoksi]valerijanska kiselina [1515][3957] Example 241: 5-[2,6-difluoro-4-(2-tetrahydropyran-4-yloxy-3-pyridyl)phenoxy]valeric acid [1515]

[3959] [3959]

[3962] Faza A: etil 5-[2,6-difluoro-4-(2-tetrahidropiran-4-iloksi-3-piridil)fenoksi] pentanoat[3962] Phase A: ethyl 5-[2,6-difluoro-4-(2-tetrahydropyran-4-yloxy-3-pyridyl)phenoxy] pentanoate

[3963] 3-jodo-2-(tetrahidropiran-4-iloksi)-piridin (0.069 g, 0.22 mmol) dobijen u primeru pripreme 58 i etil 5-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]pentanoat (0.095 g, 0.25 mmol) dobijen u primeru pripreme 225 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.071 g, 72%).[3963] 3-iodo-2-(tetrahydropyran-4-yloxy)-pyridine (0.069 g, 0.22 mmol) obtained in preparation example 58 and ethyl 5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pentanoate (0.095 g, 0.25 mmol) obtained in preparation example 58 225 were used to react in the same manner as in Step A of Example 28 to give the title compound (0.071 g, 72%).

[3964] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.58 (1H, m), 7.15 (2H, m), 6.95 (1H, m), 5.37 (1H, m), 4.20 (2H, t), 4.14 (2H, q), 3.91 (2H, m), 3.63 (2H, m), 2.41 (2H, t), 2.06 (2H, m), 1.85 (6H, m), 1.27 (3H, t)[3964] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.58 (1H, m), 7.15 (2H, m), 6.95 (1H, m), 5.37 (1H, m), 4.20 (2H, t), 4.14 (2H, q), 3.91 (2H, m), 3.63 (2H, m), 2.41 (2H, t), 2.06 (2H, m), 1.85 (6H, m), 1.27 (3H, t)

[3965] Faza B: 5-[2,6-difluoro-4-(2-tetrahidropiran-4-iloksi-3-piridil)fenoksi]valerijanska kiselina[3965] Phase B: 5-[2,6-difluoro-4-(2-tetrahydropyran-4-yloxy-3-pyridyl)phenoxy]valeric acid

[3966] Etil 5-[2,6-difluoro-4-(2-tetrahidropiran-4-iloksi-3-piridil)fenoksi] pentanoat (0.071 g, 0.16 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.054 g, 83%).[3966] Ethyl 5-[2,6-difluoro-4-(2-tetrahydropyran-4-yloxy-3-pyridyl)phenoxy] pentanoate (0.071 g, 0.16 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.054 g, 83%).

[3967] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.58 (1H, m), 7.15 (2H, m), 6.95 (1H, m), 5.38 (1H, m), 4.21 (2H, t), 3.90 (2H, m), 3.64 (2H, m), 2.47 (2H, t), 2.06 (2H, m), 1.88 (4H, m), 1.80 (2H, m)[3967] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.58 (1H, m), 7.15 (2H, m), 6.95 (1H, m), 5.38 (1H, m), 4.21 (2H, t), 3.90 (2H, m), 3.64 (2H, m), 2.47 (2H, t), 2.06 (2H, m), 1.88 (4H, m), 1.80 (2H, m)

[3969] Primer 242: 4-[2,6-difluoro-4-(2-izopropoksi-piridin-3-il)-fenilsulfanil] - valerijanska kiselina [1520][3969] Example 242: 4-[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid [1520]

[3971] [3971]

[3974] Etil estar 4-[2,6-difluoro-4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-valerijanske kiseline (0.015 g, 0.04 mmol) dobijen u primeru pripreme 219 je izreagovan na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.008 g, 57%).[3974] 4-[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid ethyl ester (0.015 g, 0.04 mmol) obtained in Preparative Example 219 was reacted in the same manner as in Step B of Example 1 to give the title compound (0.008 g, 57%).

[3975] <1>H-NMR (CDCl<3>) δ 8.16 (1H, m), 7.60 (1H, m), 7.21 (2H, d), 6.93 (1H, m), 5.40 (1H, m), 3.31 (1H, m), 2.62 (2H, m), 1.86 (2H, m), 1.36 (6H, d), 1.31 (3H, d).[3975] <1>H-NMR (CDCl<3>) δ 8.16 (1H, m), 7.60 (1H, m), 7.21 (2H, d), 6.93 (1H, m), 5.40 (1H, m), 3.31 (1H, m), 2.62 (2H, m), 1.86 (2H, m), 1.36 (6H, d), 1.31 (3H, d).

[3977] Primer 243: 4- [4-(2-ciklopentilsulfanil-piridin-3-il)-fenilsulfanil] -valerijanska kiselina[3977] Example 243: 4-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-valeric acid

[3978][3978]

[3980] [3980]

[3982] Etil estar 4-[4-(2-ciklopentilsulfanil-piridin-3-il)-fenilsulfanil]-valerijanske kiseline (0.004 g, 0.01 mmol) dobijen u primeru pripreme 217 je izreagovan na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.002 g, 54%).[3982] 4-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-valeric acid ethyl ester (0.004 g, 0.01 mmol) obtained in Preparative Example 217 was reacted in the same manner as in Step B of Example 1 to give the title compound (0.002 g, 54%).

[3983] <1>H-NMR (CDCl<3>) δ 8.41 (1H, m), 7.42 (2H, d), 7.35 (3H, m), 7.02 (1H, m), 4.06 (1H, m), 3.31 (1H, m), 2.58 (2H, m), 2.17 (2H, m), 1.93 (2H, m), 1.69-1.51 (6H, m), 1.36 (3H, d).[3983] <1>H-NMR (CDCl<3>) δ 8.41 (1H, m), 7.42 (2H, d), 7.35 (3H, m), 7.02 (1H, m), 4.06 (1H, m), 3.31 (1H, m), 2.58 (2H, m), 2.17 (2H, m), 1.93 (2H, m), 1.69-1.51 (6H, m), 1.36 (3H, d).

[3985] Primer 244: 4-{2-fluoro-4-[2-(tetrahidropiran-4-iloksi)-piridin-3-il]-fenilsulfanil}-buterna kiselina[3985] Example 244: 4-{2-fluoro-4-[2-(tetrahydropyran-4-yloxy)-pyridin-3-yl]-phenylsulfanyl}-butyric acid

[3988] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 180 i 3-jodo-2-(tetrahidropiran-4-iloksi)-piridin (0.06 g, 0.2 mmol) dobijen u primeru pripreme 58 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.03 g, 66%).[3988] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 180 and 3-iodo-2-(tetrahydropyran-4-yloxy)-pyridine (0.06 g, 0.2 mmol) obtained in Preparation Example 180 58 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.03 g, 66%).

[3989] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.62 (1H, m), 7.42 (1H, m), 7.32 (2H, m), 6.96 (1H, m), 5.37 (1H, m), 3.88 (2H, m), 3.63 (2H, m), 3.02 (2H, t), 2.56 (2H, t), 2.08 (2H, m), 1.98 (2H, m), 1.80 (2H, m)[3989] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.62 (1H, m), 7.42 (1H, m), 7.32 (2H, m), 6.96 (1H, m), 5.37 (1H, m), 3.88 (2H, m), 3.63 (2H, m), 3.02 (2H, t), 2.56 (2H, t), 2.08 (2H, m), 1.98 (2H, m), 1.80 (2H, m)

[3991] Primer 245: 4-{2-fluoro-4-[2-(tetrahidrofuran-3-iloksi)-piridin-3-il]-fenilsulfanil}-buterna kiselina [1529][3991] Example 245: 4-{2-fluoro-4-[2-(tetrahydrofuran-3-yloxy)-pyridin-3-yl]-phenylsulfanyl}-butyric acid [1529]

[3993] [3993]

[3996] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 180 i 3-jodo-2-(tetrahidrofuran-3-iloksi)-piridin (0.06 g, 0.2 mmol) dobijen u primeru pripreme 59 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.028 g, 54%).[3996] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in preparation example 180 and 3-iodo-2-(tetrahydrofuran-3-yloxy)-pyridine (0.06 g, 0.2 mmol) obtained in preparation example 59 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.028 g, 54%).

[3997] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.62 (1H, m), 7.42 (1H, m), 7.29 (2H, m), 6.98 (1H, m), 5.66 (1H, m), 4.02 (2H, m), 3.93 (2H, m), 3.03 (2H, t), 2.54 (2H, t), 2.26 (1H, m), 2.14 (1H, m), 1.95 (2H, m)[3997] <1>H-NMR (CDCl<3>) δ 8.13 (1H, m), 7.62 (1H, m), 7.42 (1H, m), 7.29 (2H, m), 6.98 (1H, m), 5.66 (1H, m), 4.02 (2H, m), 3.93 (2H, m), 3.03 (2H, t), 2.54 (2H, t), 2.26 (1H, m), 2.14 (1H, m), 1.95 (2H, m)

[3999] Primer 246: 4-[4-(2-ciklobutilmetoksi-piridin-3-il)-2-fluoro-fenilsulfanil]-buterna kiselina[3999] Example 246: 4-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric acid

[4000][4000]

[4002] [4002]

[4004] Etil estar 4-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 180 i 2-ciklobutilmetoksi-3-jodo-piridin (0.06 g, 0.2 mmol) dobijen u primeru pripreme 61 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.03 g, 60%).[4004] 4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 180 and 2-cyclobutylmethoxy-3-iodo-pyridine (0.06 g, 0.2 mmol) obtained in Preparation Example 61 were used. to react in the same manner as in steps A and B of Example 1 to give the title compound (0.03 g, 60%).

[4005] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.62 (1H, m), 7.42-7.29 (3H, m), 6.96 (1H, m), 4.32 (2H, d), 3.01 (2H, t), 2.77 (1H, m), 2.56 (2H, t), 2.09 (2H, m), 2.01-1.83 (6H, m)[4005] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.62 (1H, m), 7.42-7.29 (3H, m), 6.96 (1H, m), 4.32 (2H, d), 3.01 (2H, t), 2.77 (1H, m), 2.56 (2H, t), 2.09 (2H, m), 2.01-1.83 (6H, m)

[4007] Primer 247: 4-{2,6-difluoro-4-[2-(2,2,2-trifluoro-etoksi)-piridin-3-il]-fenilsulfanil}-buterna kiselina [1535][4007] Example 247: 4-{2,6-difluoro-4-[2-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-phenylsulfanyl}-butyric acid [1535]

[4009] [4009]

[4012] Etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.04 g, 0.1 mmol) dobijen u primeru pripreme 170 i 3-jodo-2-(2,2,2-trifluoro-etoksi)-piridin (0.05 g, 0.15 mmol) dobijen u primeru pripreme 220 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.019 g, 45%).[4012] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.04 g, 0.1 mmol) obtained in Preparation Example 170 and 3-iodo-2-(2,2,2-trifluoro-ethoxy)-pyridine (0.05 g, 0.15 mmol) obtained in Preparative Example 220 were used to react in the same manner as in Steps A and B of Example 1 to give the title compound (0.019 g, 45%).

[4013] <1>H-NMR (CDCl<3>) δ 8.17 (1H, m), 7.69 (1H, m), 7.16 (2H, d), 7.09 (1H, m), 4.82 (2H, q), 2.97 (2H, t), 2.56 (2H, t), 1.88 (2H, m)[4013] <1>H-NMR (CDCl<3>) δ 8.17 (1H, m), 7.69 (1H, m), 7.16 (2H, d), 7.09 (1H, m), 4.82 (2H, q), 2.97 (2H, t), 2.56 (2H, t), 1.88 (2H, m)

[4015] Primer 248: 4-[4-(2-ciklobutilmetoksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina [1538][4015] Example 248: 4-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid [1538]

[4017] [4017]

[4020] Etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.04 g, 0.1 mmol) dobijen u primeru pripreme 170 i 2-ciklobutilmetoksi-3-jodo-piridin (0.045 g, 0.15 mmol) dobijen u primeru pripreme 61 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.022 g, 55%).[4020] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.04 g, 0.1 mmol) obtained in preparation example 170 and 2-cyclobutylmethoxy-3-iodo-pyridine (0.045 g, 0.15 mmol) obtained in preparation example 61 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.022 g, 55%).

[4021] <1>H-NMR (CDCl<3>) δ 8.16 (1H, m), 7.61 (1H, m), 7.20 (2H, d), 6.96 (1H, m), 4.32 (2H, d), 2.95 (2H, t), 2.77 (1H, m), 2.54 (2H, t), 2.09 (2H, m), 2.01-1.83 (6H, m)[4021] <1>H-NMR (CDCl<3>) δ 8.16 (1H, m), 7.61 (1H, m), 7.20 (2H, d), 6.96 (1H, m), 4.32 (2H, d), 2.95 (2H, t), 2.77 (1H, m), 2.54 (2H, t), 2.09 (2H, m), 2.01-1.83 (6H, m)

[4023] Primer 249: 4-[4-(2-ciklopentilamino-piridin-3-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina [1541][4023] Example 249: 4-[4-(2-cyclopentylamino-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid [1541]

[4025] [4025]

[4026] Etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.04 g, 0.1 mmol) dobijen u primeru pripreme 170 i N-ciklopentil-3-jodo-piridin-2-amin (0.045 g, 0.15 mmol) dobijen u primeru pripreme 64 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.02 g, 49%).[4026] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.04 g, 0.1 mmol) obtained in Preparation Example 170 and N-cyclopentyl-3-iodo-pyridin-2-amine (0.045 g, 0.15 mmol) obtained in Preparation Example 170 64 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.02 g, 49%).

[4027] <1>H-NMR (CDCl<3>) δ 8.16 (1H, m), 7.23 (1H, m), 7.01 (2H, d), 6.63 (1H, m), 4.34 (1H, m), 2.99 (2H, t), 2.55 (2H, t), 2.07 (2H, m), 1.92 (2H, m), 1.64 (4H, m), 1.35 (2H, m)[4027] <1>H-NMR (CDCl<3>) δ 8.16 (1H, m), 7.23 (1H, m), 7.01 (2H, d), 6.63 (1H, m), 4.34 (1H, m), 2.99 (2H, t), 2.55 (2H, t), 2.07 (2H, m), 1.92 (2H, m), 1.64 (4H, m), 1.35 (2H, m)

[4029] Primer 250: 4-[2,6-difluoro-4-(2-izopropilamino-piridin-3-il)-fenilsulfanil]-buterna kiselina[4029] Example 250: 4-[2,6-difluoro-4-(2-isopropylamino-pyridin-3-yl)-phenylsulfanyl]-butyric acid

[4030][4030]

[4032] [4032]

[4035] Etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.04 g, 0.1 mmol) dobijen u primeru pripreme 170 i 3-jodo-N-izopropil-piridin-2-amin (0.04 g, 0.15 mmol) dobijen u primeru pripreme 66 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.017 g, 44%).[4035] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.04 g, 0.1 mmol) obtained in preparation example 170 and 3-iodo-N-isopropyl-pyridin-2-amine (0.04 g, 0.15 mmol) obtained in preparation example 66 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.017 g, 44%).

[4036] <1>H-NMR (CDCl<3>) δ 8.16 (1H, m), 7.23 (1H, m), 7.01 (2H, d), 6.62 (1H, m), 4.26 (1H, m), 3.00 (2H, t), 2.58 (2H, t), 1.92 (2H, m), 1.20 (6H, d)[4036] <1>H-NMR (CDCl<3>) δ 8.16 (1H, m), 7.23 (1H, m), 7.01 (2H, d), 6.62 (1H, m), 4.26 (1H, m), 3.00 (2H, t), 2.58 (2H, t), 1.92 (2H, m), 1.20 (6H, d)

[4038] Primer 251: 4-{4-[2-(ciklopropilmetil-amino)-piridin-3-il]-2,6-difluoro - fenilsulfanil}-buterna kiselina [1547][4038] Example 251: 4-{4-[2-(cyclopropylmethyl-amino)-pyridin-3-yl]-2,6-difluoro-phenylsulfanyl}-butyric acid [1547]

[4040] [4040]

[4043] Etil estar 4-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-buterne kiseline (0.04 g, 0.1 mmol) dobijen u primeru pripreme 170 i ciklopropilmetil-(3-jodo-piridin-2-il)-amin (0.043 g, 0.15 mmol) dobijen u primeru pripreme 235 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.013 g, 31%).[4043] 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-butyric acid ethyl ester (0.04 g, 0.1 mmol) obtained in Preparation Example 170 and cyclopropylmethyl-(3-iodo-pyridin-2-yl)-amine (0.043 g, 0.15 mmol) obtained in Example Preparation 235 was used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.013 g, 31%).

[4044] <1>H-NMR (CDCl<3>) δ 8.15 (1H, m), 7.25 (1H, m), 7.02 (2H, d), 6.65 (1H, m), 3.26 (2H, d), 3.00 (2H, t), 2.57 (2H, t), 1.90 (2H, m), 1.05 (1H, m), 0.50 (2H, m), 0.21 (2H, m).[4044] <1>H-NMR (CDCl<3>) δ 8.15 (1H, m), 7.25 (1H, m), 7.02 (2H, d), 6.65 (1H, m), 3.26 (2H, d), 3.00 (2H, t), 2.57 (2H, t), 1.90 (2H, m), 1.05 (1H, m), 0.50 (2H, m), 0.21 (2H, m).

[4045] Primer 252: 5-[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-valerijanska kiselina [1550][4045] Example 252: 5-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-valeric acid [1550]

[4047] [4047]

[4050] Etil estar 5-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-pentanoinske kiseline (0.055 g, 0.14 mmol) dobijen u primeru pripreme 222 i 2-ciklopentoksi-3-jodopiridin (0.06 g, 0.21 mmol) dobijen u primeru pripreme 38 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.029 g, 51%).[4050] 5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-pentanoic acid ethyl ester (0.055 g, 0.14 mmol) obtained in preparation example 222 and 2-cyclopentoxy-3-iodopyridine (0.06 g, 0.21 mmol) obtained in preparation example 38 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.029 g, 51%).

[4051] <1>H-NMR (CDCl<3>) δ 8.17 (1H, m), 7.59 (1H, m), 7.16 (2H, d), 6.92 (1H, m), 5.52 (1H, m), 2.92 (2H, t), 2.36 (2H, t), 1.95 (2H, m), 1.76 (6H, m), 1.64 (4H, m)[4051] <1>H-NMR (CDCl<3>) δ 8.17 (1H, m), 7.59 (1H, m), 7.16 (2H, d), 6.92 (1H, m), 5.52 (1H, m), 2.92 (2H, t), 2.36 (2H, t), 1.95 (2H, m), 1.76 (6H, m), 1.64 (4H, m)

[4053] Primer 253: 5-[2,6-difluoro-4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-valerijanska kiselina [1553][4053] Example 253: 5-[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid [1553]

[4055] [4055]

[4058] Etil estar 5-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-pentanoinske kiseline (0.05 g, 0.12 mmol) dobijen u primeru pripreme 222 i 3-jodo-2-izopropoksi-piridin (0.05 g, 0.19 mmol) dobijen u primeru pripreme 37 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.023 g, 48%).[4058] 5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-pentanoic acid ethyl ester (0.05 g, 0.12 mmol) obtained in Preparation Example 222 and 3-iodo-2-isopropoxy-pyridine (0.05 g, 0.19 mmol) obtained in Preparation Example 222 37 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.023 g, 48%).

[4059] <1>H-NMR (CDCl<3>) δ 8.16 (1H, m), 7.59 (1H, m), 7.18 (2H, d), 6.92 (1H, m), 5.40 (1H, m), 2.92 (2H, t), 2.36 (2H, t), 1.79 (2H, m), 1.66 (2H, m), 1.35 (6H, d)[4059] <1>H-NMR (CDCl<3>) δ 8.16 (1H, m), 7.59 (1H, m), 7.18 (2H, d), 6.92 (1H, m), 5.40 (1H, m), 2.92 (2H, t), 2.36 (2H, t), 1.79 (2H, m), 1.66 (2H, m), 1.35 (6H, d)

[4061] Primer 254: 5-[4-(2-ciklopentiloksi-piridin-3-il)-fenilsulfanil]-valerijanska kiselina[4061] Example 254: 5-[4-(2-cyclopentyloxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid

[4062][4062]

[4064] [4064]

[4066] Etil estar 5-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-valerijanske kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 224 i 2-ciklopentoksi-3-jodo-piridin (0.06 g, 0.2 mmol) dobijen u primeru pripreme 38 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.026 g, 51%).[4066] 5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-valeric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 224 and 2-cyclopentoxy-3-iodo-pyridine (0.06 g, 0.2 mmol) obtained in Preparation Example 38 were used to reacted in the same manner as in steps A and B of Example 1 to give the title compound (0.026 g, 51%).

[4067] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.56 (1H, m), 7.47 (2H, d), 7.32 (2H, d), 6.90 (1H, m), 5.49 (1H, m), 2.97 (2H, t), 2.37 (2H, t), 1.93 (2H, m), 1.82-1.65 (8H, m), 1.60 (2H, m)[4067] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.56 (1H, m), 7.47 (2H, d), 7.32 (2H, d), 6.90 (1H, m), 5.49 (1H, m), 2.97 (2H, t), 2.37 (2H, t), 1.93 (2H, m), 1.82-1.65 (8H, m), 1.60 (2H, m)

[4069] Primer 255: 5-[4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-valerijanska kiselina[4069] Example 255: 5-[4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid

[4070][4070]

[4072] [4072]

[4075] Etil estar 5-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-valerijanske kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 224 i 3-jodo-2-izopropoksi-piridin (0.054 g, 0.2 mmol) dobijen u primeru pripreme 37 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.026 g, 55%).[4075] 5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-valeric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 224 and 3-iodo-2-isopropoxy-pyridine (0.054 g, 0.2 mmol) obtained in Preparation Example 37 were used to reacted in the same manner as in steps A and B of Example 1 to give the title compound (0.026 g, 55%).

[4076] <1>H-NMR (CDCl<3>) δ 8.11 (1H, m), 7.58 (1H, m), 7.49 (2H, d), 7.32 (2H, d), 6.90 (1H, m), 5.39 (1H, m), 2.97 (2H, t), 2.39 (2H, t), 1.82-1.69 (4H, m), 1.34 (6H, d)[4076] <1>H-NMR (CDCl<3>) δ 8.11 (1H, m), 7.58 (1H, m), 7.49 (2H, d), 7.32 (2H, d), 6.90 (1H, m), 5.39 (1H, m), 2.97 (2H, t), 2.39 (2H, t), 1.82-1.69 (4H, m), 1.34 (6H, d)

[4078] Primer 256: 5-[4-(2-ciklopentilsulfanil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-valerijanska kiselina [1562][4078] Example 256: 5-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-valeric acid [1562]

[4080] [4080]

[4083] Etil estar 5-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-pentanoinske kiseline (0.05 g, 0.12 mmol) dobijen u primeru pripreme 222 i 2-ciklopentilsulfanil-3-jodopiridin (0.057 g, 0.19 mmol) dobijen u primeru pripreme 39 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.014 g, 26%).[4083] 5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-pentanoic acid ethyl ester (0.05 g, 0.12 mmol) obtained in Preparation Example 222 and 2-cyclopentylsulfanyl-3-iodopyridine (0.057 g, 0.19 mmol) obtained in Example Preparation 39 was used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.014 g, 26%).

[4084] <1>H-NMR (CDCl<3>) δ 8.45 (1H, m), 7.34 (1H, m), 7.03 (3H, m), 4.09 (1H, m), 2.93 (2H, t), 2.37 (2H, t), 2.20 (2H, m), 1.79-1.52 (10H, m)[4084] <1>H-NMR (CDCl<3>) δ 8.45 (1H, m), 7.34 (1H, m), 7.03 (3H, m), 4.09 (1H, m), 2.93 (2H, t), 2.37 (2H, t), 2.20 (2H, m), 1.79-1.52 (10H, m)

[4086] Primer 257: 5-[2,6-difluoro-4-(2-propilsulfanil-piridin-3-il)-fenilsulfanil]-valerijanska kiselina[4086] Example 257: 5-[2,6-difluoro-4-(2-propylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-valeric acid

[4088][4088]

[4090] [4090]

[4091] Etil estar 5-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-pentanoinske kiseline (0.05 g, 0.12 mmol) dobijen u primeru pripreme 222 i 3-jodo-2-propilsulfanilpiridin (0.052 g, 0.19 mmol) dobijen u primeru pripreme 203 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.023 g, 46%).[4091] 5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-pentanoic acid ethyl ester (0.05 g, 0.12 mmol) obtained in preparation example 222 and 3-iodo-2-propylsulfanylpyridine (0.052 g, 0.19 mmol) obtained in preparation example 203 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.023 g, 46%).

[4092] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.35 (1H, m), 7.03 (3H, m), 3.15 (2H, t), 2.93 (2H, t), 2.37 (2H, t), 1.80 (2H, m), 1.65 (4H, m), 1.02 (3H, t)[4092] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.35 (1H, m), 7.03 (3H, m), 3.15 (2H, t), 2.93 (2H, t), 2.37 (2H, t), 1.80 (2H, m), 1.65 (4H, m), 1.02 (3H, t)

[4094] Primer 258: 5- [4-(2-ciklopentilsulfanil-piridin-3-il)-fenilsulfanil] -valerijanska kiselina[4094] Example 258: 5-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-valeric acid

[4095][4095]

[4097] [4097]

[4100] Etil estar 5-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-valerijanske kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 224 i 2-ciklopentilsulfanil-3-jodo-piridin (0.062 g, 0.2 mmol) dobijen u primeru pripreme 39 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje(0.029 g, 54%).[4100] 5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-valeric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 224 and 2-cyclopentylsulfanyl-3-iodo-pyridine (0.062 g, 0.2 mmol) obtained in Preparation Example 39 were used. to react in the same way as in steps A and B of Example 1 to give the title compound (0.029 g, 54%).

[4101] <1>H-NMR (CDCl<3>) δ 8.40 (1H, m), 7.34 (5H, m), 7.01 (1H, m), 4.08 (1H, m), 2.98 (2H, t), 2.39 (2H, t), 2.18 (2H, m), 1.81-1.52 (10H, m)[4101] <1>H-NMR (CDCl<3>) δ 8.40 (1H, m), 7.34 (5H, m), 7.01 (1H, m), 4.08 (1H, m), 2.98 (2H, t), 2.39 (2H, t), 2.18 (2H, m), 1.81-1.52 (10H, m)

[4103] Primer 259: 5-[4-(2-ciklobutilsulfanil-piridin-3-il)-fenilsulfanil]-valerijanska kiselina[4103] Example 259: 5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-valeric acid

[4104][4104]

[4106] [4106]

[4109] Etil estar 5-[4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-valerijanske kiseline (0.05 g, 0.14 mmol) dobijen u primeru pripreme 224 i 2-ciklobutilsulfanil-3-jodo-piridin (0.06 g, 0.2 mmol) dobijen u primeru pripreme 44 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.03 g, 58%).[4109] 5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-valeric acid ethyl ester (0.05 g, 0.14 mmol) obtained in Preparation Example 224 and 2-cyclobutylsulfanyl-3-iodo-pyridine (0.06 g, 0.2 mmol) obtained in Preparation Example 44 were used to reacted in the same manner as in steps A and B of Example 1 to give the title compound (0.03 g, 58%).

[4110] <1>H-NMR (CDCl<3>) δ 8.39 (1H, m), 7.35 (5H, m), 7.01 (1H, m), 4.42 (1H, m), 2.98 (2H, t), 2.48 (2H, m), 2.40 (2H, t), 2.02 (4H, m), 1.79 (4H, m)[4110] <1>H-NMR (CDCl<3>) δ 8.39 (1H, m), 7.35 (5H, m), 7.01 (1H, m), 4.42 (1H, m), 2.98 (2H, t), 2.48 (2H, m), 2.40 (2H, t), 2.02 (4H, m), 1.79 (4H, m)

[4111] Primer 260: 5-[4-(2-ciklobutilmetoksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-valerijanska kiselina [1574][4111] Example 260: 5-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-valeric acid [1574]

[4113] [4113]

[4116] Etil estar 5-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-pentanoinske kiseline (0.05 g, 0.12 mmol) dobijen u primeru pripreme 222 i 2-ciklobutilmetoksi-3-jodopiridin (0.054 g, 0.19 mmol) dobijen u primeru pripreme 61 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.019 g, 38%).[4116] 5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-pentanoic acid ethyl ester (0.05 g, 0.12 mmol) obtained in preparation example 222 and 2-cyclobutylmethoxy-3-iodopyridine (0.054 g, 0.19 mmol) obtained in preparation example 61 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.019 g, 38%).

[4117] <1>H-NMR (CDCl<3>) δ 8.16 (1H, m), 7.62 (1H, m), 7.20 (2H, d), 6.96 (1H, m), 4.33 (2H, d), 2.92 (2H, t), 2.77 (1H, m), 2.34 (2H, t), 2.09 (2H, m), 1.87 (4H, m), 1.78 (2H, m), 1.64 (2H, m)[4117] <1>H-NMR (CDCl<3>) δ 8.16 (1H, m), 7.62 (1H, m), 7.20 (2H, d), 6.96 (1H, m), 4.33 (2H, d), 2.92 (2H, t), 2.77 (1H, m), 2.34 (2H, t), 2.09 (2H, m), 1.87 (4H, m), 1.78 (2H, m), 1.64 (2H, m)

[4119] Primer 261: 5-[4-(2-ciklobutoksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-valerijanska kiselina [1577][4119] Example 261: 5-[4-(2-cyclobutoxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-valeric acid [1577]

[4121] [4121]

[4124] Etil estar 5-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-pentanoinske kiseline (0.05 g, 0.12 mmol) dobijen u primeru pripreme 222 i 2-ciklobutoksi-3-jodo-piridin (0.052 g, 0.19 mmol) dobijen u primeru pripreme 200 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.019 g, 38%).[4124] 5-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-pentanoic acid ethyl ester (0.05 g, 0.12 mmol) obtained in preparation example 222 and 2-cyclobutoxy-3-iodo-pyridine (0.052 g, 0.19 mmol) obtained in preparation example 200 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.019 g, 38%).

[4125] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.60 (1H, m), 7.21 (2H, d), 6.94 (1H, m), 5.27 (1H, m), 2.92 (2H, t), 2.47 (2H, m), 2.36 (2H, t), 2.12 (2H, m), 1.80 (3H, m), 1.65 (3H, m)[4125] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.60 (1H, m), 7.21 (2H, d), 6.94 (1H, m), 5.27 (1H, m), 2.92 (2H, t), 2.47 (2H, m), 2.36 (2H, t), 2.12 (2H, m), 1.80 (3H, m), 1.65 (3H, m)

[4127] Primer 262: 6-[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenoksi]-kapronska kiselina[4127] Example 262: 6-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-caproic acid

[4128][4128]

[4130] [4130]

[4133] Etil estar 6-bromo-kapronske kiseline (46 mg, 0.21 mmol) i 4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenol (50 mg, 0.17 mmol) dobijen u primeru pripreme 55 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 232 da bi se dobilo naslovno jedinjenje (43 mg, 62 %).[4133] 6-Bromo-caproic acid ethyl ester (46 mg, 0.21 mmol) and 4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenol (50 mg, 0.17 mmol) obtained in Preparation Example 55 were used to react in the same manner as in steps A and B of Example 232 to give the title compound (43 mg, 62 %).

[4134] 1H NMR (CDCl<3>) δ 8.15 (1H, m), 7.56 (1H, m), 7.14 (2H, m), 6.91 (1H, m), 5.51 (1H, m), 4.19 (2H, t), 2.41 (2H, t), 1.95 (2H, m), 1.83 (4H, m), 1.74 (4H, m), 1.57 (4H, m)[4134] 1H NMR (CDCl<3>) δ 8.15 (1H, m), 7.56 (1H, m), 7.14 (2H, m), 6.91 (1H, m), 5.51 (1H, m), 4.19 (2H, t), 2.41 (2H, t), 1.95 (2H, m), 1.83 (4H, m), 1.74 (4H, m), 1.57 (4H, m)

[4136] Primer 263: 7-[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenoksi]-enantna kiselina[4136] Example 263: 7-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-enanoic acid

[4137][4137]

[4139] [4139]

[4142] Etil estar 7-bromo-enantne kiseline (49 mg, 0.21 mmol) i 4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenol (50 mg, 0.17 mmol) dobijen u primeru pripreme 55 su korišćeni da bi reagovali na isti način kao u fazi C primera pripreme 2 da bi se dobilo naslovno jedinjenje (45 mg, 59 %).[4142] 7-Bromo-enanoic acid ethyl ester (49 mg, 0.21 mmol) and 4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenol (50 mg, 0.17 mmol) obtained in Preparative Example 55 were used to react in the same manner as in Step C of Preparative Example 2 to give the title compound (45 mg, 59%).

[4143] 1H NMR (CDCl<3>) δ 8.14 (1H, m), 7.57 (1H, m), 7.14 (2H, m), 6.91 (1H, m), 5.52 (1H, m), 4.18 (2H, t), 2.39 (2H, t), 1.95 (2H, m), 1.85-1.40 (14H, m)[4143] 1H NMR (CDCl<3>) δ 8.14 (1H, m), 7.57 (1H, m), 7.14 (2H, m), 6.91 (1H, m), 5.52 (1H, m), 4.18 (2H, t), 2.39 (2H, t), 1.95 (2H, m), 1.85-1.40 (14H, m)

[4145] Primer 264: 5-[2-fluoro-4-(2-izopropoksi-piridin-3-il)-fenoksi]-valerijanska kiselina[4145] Example 264: 5-[2-fluoro-4-(2-isopropoxy-pyridin-3-yl)-phenoxy]-valeric acid

[4146][4146]

[4148] [4148]

[4151] 3-jodo-2-izopropoksi-piridin (0.030 g, 0.11 mmol) dobijen u primeru pripreme 37 i etil estar 5-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenoksi]-valerijanske kiseline (0.042 g, 0.11 mmol) dobijen u primeru pripreme 147 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.023 g, 58 %).[4151] 3-iodo-2-isopropoxy-pyridine (0.030 g, 0.11 mmol) obtained in preparation example 37 and 5-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-valeric acid ethyl ester (0.042 g, 0.11 mmol) obtained in preparation example 147 were used. to react in the same way as in steps A and B of Example 1 to give the title compound (0.023 g, 58 %).

[4152] 1H NMR (CDCl<3>) δ 8.10 (1H, m), 7.55 (1H, m), 7.38 (1H, m), 7.25 (1H, d), 6.97 (1H, t), 6.90 (1H, m), 5.40 (1H, m), 4.10 (2H, t), 2.49 (2H, t), 1.91(4H, m), 1.43 (6H, d)[4152] 1H NMR (CDCl<3>) δ 8.10 (1H, m), 7.55 (1H, m), 7.38 (1H, m), 7.25 (1H, d), 6.97 (1H, t), 6.90 (1H, m), 5.40 (1H, m), 4.10 (2H, t), 2.49 (2H, t), 1.91(4H, m), 1.43 (6H, d)

[4154] Primer 265: 5-[4-(2-ciklopentilsulfanil-piridin-3-il)-2-fluoro-fenoksi]-valerijanska kiselina[4154] Example 265: 5-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2-fluoro-phenoxy]-valeric acid

[4155][4155]

[4157] [4157]

[4160] 2-ciklopentilsulfanil-3-jodo-piridin (0.030 g, 0.10 mmol) dobijen u primeru pripreme 39 i etil estar 5-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenoksi]-valerijanske kiseline (0.036 g, 0.10 mmol) dobijen u primeru pripreme 147 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.026 g, 68 %).[4160] 2-cyclopentylsulfanyl-3-iodo-pyridine (0.030 g, 0.10 mmol) obtained in preparation example 39 and 5-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-valeric acid ethyl ester (0.036 g, 0.10 mmol) obtained in preparation example 147 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.026 g, 68 %).

[4161] 1H NMR (CDCl<3>) δ 8.41 (1H, m), 7.32 (1H, m), 7.17 (1H, m), 7.12 (1H, d), 7.01 (2H, m), 4.10 (3H, m), 2.49 (2H, t), 2.19 (2H, m), 1.91 (4H, m), 1.75-1.50 (6H, m)[4161] 1H NMR (CDCl<3>) δ 8.41 (1H, m), 7.32 (1H, m), 7.17 (1H, m), 7.12 (1H, d), 7.01 (2H, m), 4.10 (3H, m), 2.49 (2H, t), 2.19 (2H, m), 1.91 (4H, m), 1.75-1.50 (6H, m)

[4163] Primer 266: 5-[4-(2-ciklobutilsulfanil-piridin-3-il)-2-fluoro-fenoksi]-valerijanska kiselina[4163] Example 266: 5-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2-fluoro-phenoxy]-valeric acid

[4164][4164]

[4166] [4166]

[4169] 2-ciklobutilsulfanil-3-jodo-piridin (0.030 g, 0.10 mmol) dobijen u primeru pripreme 44 i etil estar 5-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenoksi]-valerijanske kiseline (0.038 g, 0.10 mmol) dobijen u primeru pripreme 147 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.024 g, 62 %).[4169] 2-cyclobutylsulfanyl-3-iodo-pyridine (0.030 g, 0.10 mmol) obtained in preparation example 44 and 5-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-valeric acid ethyl ester (0.038 g, 0.10 mmol) obtained in preparation example 147 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.024 g, 62 %).

[4170] 1H NMR (CDCl<3>) δ 8.39 (1H, m), 7.34 (1H, m), 7.15 (2H, m), 7.02 (2H, m), 4.43 (1H, m), 4.11 (2H, t), 2.50 (4H, m), 2.04 (4H, m), 1.92 (4H, m)[4170] 1H NMR (CDCl<3>) δ 8.39 (1H, m), 7.34 (1H, m), 7.15 (2H, m), 7.02 (2H, m), 4.43 (1H, m), 4.11 (2H, t), 2.50 (4H, m), 2.04 (4H, m), 1.92 (4H, m)

[4172] Primer 267: 5-[4-(2-ciklopentiloksi-piridin-3-il)-2-fluoro-fenoksi]-valerijanska kiselina[4172] Example 267: 5-[4-(2-cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenoxy]-valeric acid

[4173][4173]

[4175] [4175]

[4178] 2-ciklopentoksi-3-jodo-piridin (0.030 g, 0.10 mmol) dobijen u primeru pripreme 38 i etil estar 5-[2-fluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenoksi]-valerijanske kiseline (0.038 g, 0.10 mmol) dobijen u primeru pripreme 147 su korišćeni da bi reagovali na isti način kao u primeru 1 da bi se dobilo naslovno jedinjenje (0.026 g, 67 %).[4178] 2-cyclopentoxy-3-iodo-pyridine (0.030 g, 0.10 mmol) obtained in Preparation Example 38 and 5-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-valeric acid ethyl ester (0.038 g, 0.10 mmol) obtained in Preparation Example 147 were used. to react in the same way as in Example 1 to give the title compound (0.026 g, 67 %).

[4179] 1H NMR (CDCl<3>) δ 8.11 (1H, m), 7.57 (1H, m), 7.34 (1H, m), 7.25 (1H, m), 6.96 (1H, t), 6.90 (1H, m), 5.51 (1H, m), 4.10 (2H, t), 2.49 (2H, t), 2.00-1.60 (12H, m)[4179] 1H NMR (CDCl<3>) δ 8.11 (1H, m), 7.57 (1H, m), 7.34 (1H, m), 7.25 (1H, m), 6.96 (1H, t), 6.90 (1H, m), 5.51 (1H, m), 4.10 (2H, t), 2.49 (2H, t), 2.00-1.60 (12H, m)

[4180] Primer 268: 4-[2,6-difluoro-4-(2-metoksi-piridin-3-il)-fenoksi]-buterna kiselina[4180] Example 268: 4-[2,6-difluoro-4-(2-methoxy-pyridin-3-yl)-phenoxy]-butyric acid

[4181][4181]

[4183] [4183]

[4186] Metanol (26 mg, 0.80 mmol) i 4-[2,6-difluoro-4-(2-fluoro-3-piridil)fenoksi]buterna kiselina (50 mg, 0.16 mmol) dobijena u primeru pripreme 56 su korišćeni da bi reagovali na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (35 mg, 67 %).[4186] Methanol (26 mg, 0.80 mmol) and 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butyric acid (50 mg, 0.16 mmol) obtained in Preparative Example 56 were used to react in the same manner as in Preparative Example 37 to give the title compound (35 mg, 67%).

[4187] 1H NMR (CDCl<3>) δ 8.17 (1H, m), 7.57 (1H, m), 7.14 (2H, m), 6.98 (1H, m), 4.24 (2H, t), 3.98 (3H, s), 2.68 (2H, t), 2.13 (2H, m)[4187] 1H NMR (CDCl<3>) δ 8.17 (1H, m), 7.57 (1H, m), 7.14 (2H, m), 6.98 (1H, m), 4.24 (2H, t), 3.98 (3H, s), 2.68 (2H, t), 2.13 (2H, m)

[4189] Primer 269: 4-[4-(2-aliloksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina[4189] Example 269: 4-[4-(2-allyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid

[4190][4190]

[4192] [4192]

[4195] Prop-2-en-1-ol (47 mg, 0.80 mmol) i 4-[2,6-difluoro-4-(2-fluoro-3-piridil)fenoksi]buterna kiselina (50 mg, 0.16 mmol) dobijena u primeru pripreme 56 su korišćeni da bi reagovali na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (7 mg, 12 %).[4195] Prop-2-en-1-ol (47 mg, 0.80 mmol) and 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butyric acid (50 mg, 0.16 mmol) obtained in Preparative Example 56 were used to react in the same manner as in Preparative Example 37 to give the title compound (7 mg, 12%).

[4196] 1H NMR (CDCl<3>) δ 8.15 (1H, m), 7.58 (1H, m), 7.15 (2H, m), 6.98 (1H, m), 6.09 (1H, m), 5.36 (1H, m), 5.24 (1H, m), 4.91 (2H, m), 4.24 (2H, t), 2.68 (2H, t), 2.13 (2H, m)[4196] 1H NMR (CDCl<3>) δ 8.15 (1H, m), 7.58 (1H, m), 7.15 (2H, m), 6.98 (1H, m), 6.09 (1H, m), 5.36 (1H, m), 5.24 (1H, m), 4.91 (2H, m), 4.24 (2H, t), 2.68 (2H, t), 2.13 (2H, m)

[4198] Primer 270: 4-[4-(2-but-2-iniloksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina[4198] Example 270: 4-[4-(2-but-2-ynyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid

[4199][4199]

[4201] [4201]

[4203] But-2-in-1-ol (47 mg, 0.80 mmol) i 4-[2,6-difluoro-4-(2-fluoro-3-piridil)fenoksi]buterna kiselina (50 mg, 0.16 mmol) dobijena u primeru pripreme 56 su korišćeni da bi reagovali na isti način kao u primeru pripreme 37 da bi se dobilo naslovno jedinjenje (35 mg, 60 %).[4203] But-2-yn-1-ol (47 mg, 0.80 mmol) and 4-[2,6-difluoro-4-(2-fluoro-3-pyridyl)phenoxy]butyric acid (50 mg, 0.16 mmol) obtained in Preparative Example 56 were used to react in the same manner as in Preparative Example 37 to give the title compound (35 mg, 60%).

[4204] 1H NMR (CDCl<3>) δ 8.17 (1H, m), 7.58 (1H, m), 7.17 (2H, m), 7.00 (1H, m), 5.00 (2H, m), 4.24 (2H, t), 2.68 (2H, t), 2.13 (2H, m), 1.85 (3H, t)[4204] 1H NMR (CDCl<3>) δ 8.17 (1H, m), 7.58 (1H, m), 7.17 (2H, m), 7.00 (1H, m), 5.00 (2H, m), 4.24 (2H, t), 2.68 (2H, t), 2.13 (2H, m), 1.85 (3H, t)

[4206] Primer 271: 6-[4-[2-(ciklobutoksi)-3-piridil]-2,6-difluoro-fenoksi] kapronska kiselina[4206] Example 271: 6-[4-[2-(cyclobutoxy)-3-pyridyl]-2,6-difluoro-phenoxy] caproic acid

[4207][4207]

[4209] [4209]

[4212] Faza A: etil 6-[4-[2-(ciklobutoksi)-3-piridil]-2,6-difluoro-fenoksi]heksanoat[4212] Phase A: ethyl 6-[4-[2-(cyclobutoxy)-3-pyridyl]-2,6-difluoro-phenoxy]hexanoate

[4213] 2-ciklobutoksi-3-jodo-piridin (0.072 g, 0.26 mmol) dobijen u primeru pripreme 200 i etil 6-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]heksanoat (0.11 g, 0.27 mmol) dobijen u primeru pripreme 146 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.064 g, 59%).[4213] 2-cyclobutoxy-3-iodo-pyridine (0.072 g, 0.26 mmol) obtained in Preparation Example 200 and ethyl 6-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]hexanoate (0.11 g, 0.27 mmol) obtained in Preparation Example 146 were used to would react in the same manner as in step A of Example 28 to give the title compound (0.064 g, 59%).

[4214] <1>H-NMR (CDCl<3>) δ 8.11 (1H, m), 7.56 (1H, m), 7.20 (2H, m), 6.93 (1H, m), 5.28 (1H, m), 4.15 (4H, m), 2.49 (2H, m), 2.44 (2H, t), 2.14 (2H, m), 1.82 (3H, m), 1.72 (3H, m), 1.55 (2H, m), 1.26 (3H, t)[4214] <1>H-NMR (CDCl<3>) δ 8.11 (1H, m), 7.56 (1H, m), 7.20 (2H, m), 6.93 (1H, m), 5.28 (1H, m), 4.15 (4H, m), 2.49 (2H, m), 2.44 (2H, t), 2.14 (2H, m), 1.82 (3H, m), 1.72 (3H, m), 1.55 (2H, m), 1.26 (3H, t)

[4216] Faza B: 6-[4-[2-(ciklobutoksi)-3-piridil]-2,6-difluoro-fenoksi]kapronska kiselina[4216] Phase B: 6-[4-[2-(cyclobutoxy)-3-pyridyl]-2,6-difluoro-phenoxy]caproic acid

[4217] Etil 6-[4-[2-(ciklobutoksi)-3-piridil]-2,6-difluoro-fenoksi]heksanoat (0.064 g, 0.15 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.058 g, 97%).[4217] Ethyl 6-[4-[2-(cyclobutoxy)-3-pyridyl]-2,6-difluoro-phenoxy]hexanoate (0.064 g, 0.15 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.058 g, 97%).

[4218] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.57 (1H, m), 7.17 (2H, m), 6.93 (1H, m), 5.27 (1H, m), 4.18 (2H, t), 2.48 (2H, m), 1.41 (2H, t), 2.14 (2H, m), 1.83 (3H, m), 1.71 (3H, m), 1.59 (2H, m),[4218] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.57 (1H, m), 7.17 (2H, m), 6.93 (1H, m), 5.27 (1H, m), 4.18 (2H, t), 2.48 (2H, m), 1.41 (2H, t), 2.14 (2H, m), 1.83 (3H, m), 1.71 (3H, m), 1.59 (2H, m),

[4220] Primer 272: 6-[4-[2-(ciklobutilmetoksi)-3-piridil]-2,6-difluoro-fenoksi]kapronska kiselina[4220] Example 272: 6-[4-[2-(cyclobutylmethoxy)-3-pyridyl]-2,6-difluoro-phenoxy]caproic acid

[4221][4221]

[4223] [4223]

[4226] Faza A: etil 6-[4-[2-(ciklobutilmetoksi)-3-piridil]-2,6-difluoro-fenoksi] heksanoat[4226] Phase A: ethyl 6-[4-[2-(cyclobutylmethoxy)-3-pyridyl]-2,6-difluoro-phenoxy] hexanoate

[4227] 2-ciklobutilmetoksi-3-jodo-piridin (0.076 g, 0.26 mmol) dobijen u primeru pripreme 61 i etil 6-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]heksanoat (0.11 g, 0.27 mmol) dobijen u primeru pripreme 146 su korišćeni da bi reagovali na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.058 g, 97%).[4227] 2-cyclobutylmethoxy-3-iodo-pyridine (0.076 g, 0.26 mmol) obtained in Preparation Example 61 and ethyl 6-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]hexanoate (0.11 g, 0.27 mmol) obtained in Preparation Example 146 were used to would react in the same way as in phase B of Example 1 to give the title compound (0.058 g, 97%).

[4228] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.58 (1H, m), 7.17 (2H, m), 6.95 (1H, m), 4.32 (2H, d), 4.15 (4H, m), 2.80 (1H, m), 2.34 (2H, t), 2.10 (2H, m), 1.92 (4H, m), 1.82 (2H, m), 1.75 (2H, m), 1.54 (2H, m), 1.26 (3H, t)[4228] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.58 (1H, m), 7.17 (2H, m), 6.95 (1H, m), 4.32 (2H, d), 4.15 (4H, m), 2.80 (1H, m), 2.34 (2H, t), 2.10 (2H, m), 1.92 (4H, m), 1.82 (2H, m), 1.75 (2H, m), 1.54 (2H, m), 1.26 (3H, t)

[4230] Faza B: 6-[4-[2-(ciklobutilmetoksi)-3-piridil]-2,6-difluoro-fenoksi]kapronska kiselina[4230] Phase B: 6-[4-[2-(cyclobutylmethoxy)-3-pyridyl]-2,6-difluoro-phenoxy]caproic acid

[4231] Etil 6-[4-[2-(ciklobutilmetoksi)-3-piridil]-2,6-difluoro-fenoksi]heksanoat (0.064 g, 0.15 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.067 g, 99%).[4231] Ethyl 6-[4-[2-(cyclobutylmethoxy)-3-pyridyl]-2,6-difluoro-phenoxy]hexanoate (0.064 g, 0.15 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.067 g, 99%).

[4232] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.58 (1H, m), 7.17 (2H, m), 6.93 (1H, m), 4.32 (2H, d), 4.17 (2H, t), 2.78 (1H, m), 2.41 (2H, t), 2.10 (2H, m), 1.89 (2H, m), 1.96 (1H, m), 1.88 (3H, m), 1.82 (2H, m), 1.73 (2H, m)[4232] <1>H-NMR (CDCl<3>) δ 8.14 (1H, m), 7.58 (1H, m), 7.17 (2H, m), 6.93 (1H, m), 4.32 (2H, d), 4.17 (2H, t), 2.78 (1H, m), 2.41 (2H, t), 2.10 (2H, m), 1.89 (2H, m), 1.96 (1H, m), 1.88 (3H, m), 1.82 (2H, m), 1.73 (2H, m)

[4234] Primer 273: 6-[4-[2-(ciklopropilmetoksi)-3-piridil]-2,6-difluoro-fenoksi]kapronska kiselina[4234] Example 273: 6-[4-[2-(cyclopropylmethoxy)-3-pyridyl]-2,6-difluoro-phenoxy]caproic acid

[4235][4235]

[4237] [4237]

[4240] Faza A: etil 6-[4-[2-(ciklopropilmetoksi)-3-piridil]-2,6-difluoro-fenoksi] heksanoat[4240] Phase A: ethyl 6-[4-[2-(cyclopropylmethoxy)-3-pyridyl]-2,6-difluoro-phenoxy] hexanoate

[4241] 2-ciklopropilmetoksi-3-jodo-piridin (0.072 g, 0.26 mmol) dobijen u primeru pripreme 40 i etil 6-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]heksanoat (0.11 g, 0.27 mmol) dobijen u primeru pripreme 146 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.075 g, 69%).[4241] 2-Cyclopropylmethoxy-3-iodo-pyridine (0.072 g, 0.26 mmol) obtained in Preparation Example 40 and ethyl 6-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]hexanoate (0.11 g, 0.27 mmol) obtained in Preparation Example 146 were used to would react in the same manner as in step A of Example 28 to give the title compound (0.075 g, 69%).

[4242] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.59 (1H, m), 7.23 (2H, m), 6.94 (1H, m), 4.22 (2H, d), 4.15 (4H, m), 2.34 (2H, t), 1.80 (2H, m), 1.72 (2H, m), 1.55 (2H, m), 1.26 (4H, m), 0.60 (2H, m), 0.35 (2H, m)[4242] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.59 (1H, m), 7.23 (2H, m), 6.94 (1H, m), 4.22 (2H, d), 4.15 (4H, m), 2.34 (2H, t), 1.80 (2H, m), 1.72 (2H, m), 1.55 (2H, m), 1.26 (4H, m), 0.60 (2H, m), 0.35 (2H, m)

[4244] Faza B: 6-[4-[2-(ciklopropilmetoksi)-3-piridil]-2,6-difluoro-fenoksi]kapronska kiselina[4244] Phase B: 6-[4-[2-(cyclopropylmethoxy)-3-pyridyl]-2,6-difluoro-phenoxy]caproic acid

[4245] Etil 6-[4-[2-(ciklopropilmetoksi)-3-piridil]-2,6-difluoro-fenoksi]heksanoat (0.075 g, 0.18 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.049 g, 69%).[4245] Ethyl 6-[4-[2-(cyclopropylmethoxy)-3-pyridyl]-2,6-difluoro-phenoxy]hexanoate (0.075 g, 0.18 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.049 g, 69%).

[4246] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.58 (1H, m), 7.22 (2H, m), 6.95 (1H, m), 4.22 (2H, d), 4.18 (2H, t), 2.41 (2H, t), 1.82 (2H, m), 1.73 (2H, m), 1.58 (2H, m), 1.31 (1H, m), 0.60 (2H, m), 0.35 (2H, m) Primer 274: 6-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi] kapronska kiselina[4246] <1>H-NMR (CDCl<3>) δ 8.12 (1H, m), 7.58 (1H, m), 7.22 (2H, m), 6.95 (1H, m), 4.22 (2H, d), 4.18 (2H, t), 2.41 (2H, t), 1.82 (2H, m), 1.73 (2H, m), 1.58 (2H, m), 1.31 (1H, m), 0.60 (2H, m), 0.35 (2H, m) Example 274: 6-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy] caproic acid

[4247][4247]

[4249] [4249]

[4252] Faza A: etil 6-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]heksanoat[4252] Phase A: ethyl 6-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]hexanoate

[4253] 2-ciklobutilsulfanil-3-jodo-piridin (0.076 g, 0.26 mmol) dobijen u primeru pripreme 44 i etil 6-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]heksanoat (0.11 g, 0.27 mmol) dobijen u primeru pripreme 146 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.067 g, 59%).[4253] 2-cyclobutylsulfanyl-3-iodo-pyridine (0.076 g, 0.26 mmol) obtained in Preparation Example 44 and ethyl 6-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]hexanoate (0.11 g, 0.27 mmol) obtained in Preparation Example 146 were used. to react in the same manner as in Step A of Example 28 to give the title compound (0.067 g, 59%).

[4254] <1>H-NMR (CDCl<3>) δ 8.41 (1H, m), 7.33 (1H, m), 7.03 (1H, m), 6.95 (2H, m), 4.43 (1H, m), 4.19 (2H, t), 4.14 (2H, q), 2.52 (2H, m), 2.35 (2H, t), 2.06 (4H, m), 1.82 (2H, m), 1.73 (2H, m), 1.55 (2H, m), 1.26 (3H, t)[4254] <1>H-NMR (CDCl<3>) δ 8.41 (1H, m), 7.33 (1H, m), 7.03 (1H, m), 6.95 (2H, m), 4.43 (1H, m), 4.19 (2H, t), 4.14 (2H, q), 2.52 (2H, m), 2.35 (2H, t), 2.06 (4H, m), 1.82 (2H, m), 1.73 (2H, m), 1.55 (2H, m), 1.26 (3H, t)

[4256] Faza B: 6-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]kapronska kiselina[4256] Phase B: 6-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]caproic acid

[4257] Etil 6-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]heksanoat (0.067 g, 0.15 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.057 g, 91%).[4257] Ethyl 6-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]hexanoate (0.067 g, 0.15 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.057 g, 91%).

[4258] <1>H-NMR (CDCl<3>) δ 8.41 (1H, m), 7.32 (1H, m), 7.02 (1H, m), 6.99 (2H, m), 4.42 (1H, m), 4.19 (2H, t), 2.52 (2H, m), 2.42 (2H, t), 2.05 (4H, m), 1.82 (2H, m), 1.74 (2H, m), 1.58 (2H, m)[4258] <1>H-NMR (CDCl<3>) δ 8.41 (1H, m), 7.32 (1H, m), 7.02 (1H, m), 6.99 (2H, m), 4.42 (1H, m), 4.19 (2H, t), 2.52 (2H, m), 2.42 (2H, t), 2.05 (4H, m), 1.82 (2H, m), 1.74 (2H, m), 1.58 (2H, m)

[4260] Primer 275: 6-[4-(2-ciklopentilsulfanil-3-piridil)-2,6-difluoro-fenoksi] kapronska kiselina[4260] Example 275: 6-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy] caproic acid

[4261][4261]

[4263] [4263]

[4266] Faza A: etil 6-[4-(2-ciklopentilsulfanil-3-piridil)-2,6-difluoro-fenoksi] heksanoat[4266] Phase A: ethyl 6-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy] hexanoate

[4267] 2-ciklopentilsulfanil-3-jodo-piridin (0.079 g, 0.26 mmol) dobijen u primeru pripreme 39 i etil 6-[2,6-difluoro-4-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2-il)fenoksi]heksanoat (0.11 g, 0.27 mmol) dobijen u primeru pripreme 146 su korišćeni da bi reagovali na isti način kao u fazi A primera 28 da bi se dobilo naslovno jedinjenje (0.080 g, 68%).[4267] 2-cyclopentylsulfanyl-3-iodo-pyridine (0.079 g, 0.26 mmol) obtained in preparation example 39 and ethyl 6-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]hexanoate (0.11 g, 0.27 mmol) obtained in preparation example 146 were used to react in the same manner as in Step A of Example 28 to give the title compound (0.080 g, 68%).

[4268] <1>H-NMR (CDCl<3>) δ 8.43 (1H, m), 7.32 (1H, m), 7.03 (1H, m), 6.98 (2H, m), 4.20 (2H, t), 4.13 (3H, m), 2.34 (2H, t), 2.20 (2H, m), 1.82 (2H, m), 1.72 (4H, m), 1.65 (2H, m), 1.59 (4H, m), 1.26 (3H, t)[4268] <1>H-NMR (CDCl<3>) δ 8.43 (1H, m), 7.32 (1H, m), 7.03 (1H, m), 6.98 (2H, m), 4.20 (2H, t), 4.13 (3H, m), 2.34 (2H, t), 2.20 (2H, m), 1.82 (2H, m), 1.72 (4H, m), 1.65 (2H, m), 1.59 (4H, m), 1.26 (3H, t)

[4269] Faza B: 6-[4-(2-ciklopentilsulfanil-3-piridil)-2,6-difluoro-fenoksi]kapronska kiselina[4269] Phase B: 6-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]caproic acid

[4270] Etil 6-[4-(2-ciklopentilsulfanil-3-piridil)-2,6-difluoro-fenoksi]heksanoat (0.080 g, 0.17 mmol) dobijen u fazi A je korišćen da bi reagovao na isti način kao u fazi B primera 1 da bi se dobilo naslovno jedinjenje (0.067 g, 89%).[4270] Ethyl 6-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]hexanoate (0.080 g, 0.17 mmol) obtained in Step A was used to react in the same manner as in Step B of Example 1 to give the title compound (0.067 g, 89%).

[4271] <1>H-NMR (CDCl<3>) δ 8.43 m), 7.33 m), 7.03 m), 6.98 (2H, m), 4.19 (2H, t), 4.10 m), 2.41 (2H, t), 2.20 (2H, m), 1.83 (2H, m), 1.73 (4H, m), 1.63 (2H, m), 1.56 (4H, m)[4271] <1>H-NMR (CDCl<3>) δ 8.43 m), 7.33 m), 7.03 m), 6.98 (2H, m), 4.19 (2H, t), 4.10 m), 2.41 (2H, t), 2.20 (2H, m), 1.83 (2H, m), 1.73 (4H, m), 1.63 (2H, m), 1.56 (4H, m)

[4273] Primer 276: 6-[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-kapronska kiselina [1632][4273] Example 276: 6-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-caproic acid [1632]

[4275] [4275]

[4278] Etil estar 6-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-kapronske kiseline (0.05 g, 0.12 mmol) dobijen u primeru pripreme 237 i 2-ciklopentoksi-3-jodo-piridin(0.052 g, 0.18 mmol) dobijen u primeru pripreme 38 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.029 g, 58%).[4278] 6-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-caproic acid ethyl ester (0.05 g, 0.12 mmol) obtained in preparation example 237 and 2-cyclopentoxy-3-iodo-pyridine (0.052 g, 0.18 mmol) obtained in preparation example 38 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.029 g, 58%).

[4279] <1>H-NMR (CDCl<3>) δ 8.17 m), 7.59 m), 7.16 (2H, d), 6.92 m), 5.52 m), 2.90 (2H, t), 2.33 (2H, t), 1.94 (2H, m), 1.82-1.71 (4H, m), 1.63 (6H, m), 1.48 (2H, m).[4279] <1>H-NMR (CDCl<3>) δ 8.17 m), 7.59 m), 7.16 (2H, d), 6.92 m), 5.52 m), 2.90 (2H, t), 2.33 (2H, t), 1.94 (2H, m), 1.82-1.71 (4H, m), 1.63 (6H, m), 1.48 (2H, m).

[4281] Primer 277: 6-[4-(2-ciklopentilsulfanil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-kapronska kiselina [1635][4281] Example 277: 6-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-caproic acid [1635]

[4283] [4283]

[4286] Etil estar 6-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-kapronske kiseline (0.05 g, 0.12 mmol) dobijen u primeru pripreme 237 i 2-ciklopentilsulfanil-3-jodo-piridin (0.055 g, 0.18 mmol) dobijen u primeru pripreme 39 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.032 g, 60%).[4286] 6-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-caproic acid ethyl ester (0.05 g, 0.12 mmol) obtained in Preparation Example 237 and 2-cyclopentylsulfanyl-3-iodo-pyridine (0.055 g, 0.18 mmol) obtained in of Preparative Example 39 were used to react in the same manner as in Steps A and B of Example 1 to give the title compound (0.032 g, 60%).

[4287] <1>H-NMR (CDCl<3>) δ 8.44 m), 7.34 (1H, m), 7.02 (3H, m), 4.08 (1H, m), 2.91 (2H, t), 2.34 (2H, t), 2.19 (2H, m), 1.78-1.48 (12H, m).[4287] <1>H-NMR (CDCl<3>) δ 8.44 m), 7.34 (1H, m), 7.02 (3H, m), 4.08 (1H, m), 2.91 (2H, t), 2.34 (2H, t), 2.19 (2H, m), 1.78-1.48 (12H, m).

[4289] Primer 278: 6-[4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-kapronska kiselina[4289] Example 278: 6-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-caproic acid

[4292] Etil estar 6-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-kapronske kiseline (0.05 g, 0.12 mmol) dobijen u primeru pripreme 237 i 2-ciklobutilsulfanil-3-jodo-piridin (0.053 g, 0.18 mmol) dobijen u primeru pripreme 44 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.029 g, 56%).[4292] 6-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-caproic acid ethyl ester (0.05 g, 0.12 mmol) obtained in Preparation Example 237 and 2-cyclobutylsulfanyl-3-iodo-pyridine (0.053 g, 0.18 mmol) obtained in Example Preparation 44 was used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.029 g, 56%).

[4293] <1>H-NMR (CDCl<3>) δ 8.42 (1H, m), 7.35 (1H, m), 7.02 (3H, m), 4.42 (1H, m), 2.92 (2H, t), 2.49 (2H, m), 2.35 (2H, t), 2.03 (4H, m), 1.63 (4H, m), 1.49 (2H, m).[4293] <1>H-NMR (CDCl<3>) δ 8.42 (1H, m), 7.35 (1H, m), 7.02 (3H, m), 4.42 (1H, m), 2.92 (2H, t), 2.49 (2H, m), 2.35 (2H, t), 2.03 (4H, m), 1.63 (4H, m), 1.49 (2H, m).

[4295] Primer 279: 6-[2,6-difluoro-4-(2-propilsulfanil-piridin-3-il)-fenilsulfanil]-kapronska kiselina[4295] Example 279: 6-[2,6-difluoro-4-(2-propylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-caproic acid

[4296][4296]

[4298] [4298]

[4301] Etil estar 6-[2,6-difluoro-4-(4,4,5,5-tetrametil-[1,3,2]dioksaborolan-2-il)-fenilsulfanil]-kapronske kiseline (0.05 g, 0.12 mmol) dobijen u primeru pripreme 237 i 3-jodo-2-propilsulfanil-piridin (0.05 g, 0.18 mmol) dobijen u primeru pripreme 203 su korišćeni da bi reagovali na isti način kao u fazama A i B primera 1 da bi se dobilo naslovno jedinjenje (0.027 g, 55%).[4301] 6-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylsulfanyl]-caproic acid ethyl ester (0.05 g, 0.12 mmol) obtained in preparation example 237 and 3-iodo-2-propylsulfanyl-pyridine (0.05 g, 0.18 mmol) obtained in preparation example 203 were used to react in the same manner as in steps A and B of Example 1 to give the title compound (0.027 g, 55%).

[4302] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.35 (1H, m), 7.03 (3H, m), 3.14 (2H, t), 2.92 (2H, t), 2.34 (2H, t), 1.69-1.62 (6H, m), 1.49 (2H, m), 1.02 (3H, t).[4302] <1>H-NMR (CDCl<3>) δ 8.44 (1H, m), 7.35 (1H, m), 7.03 (3H, m), 3.14 (2H, t), 2.92 (2H, t), 2.34 (2H, t), 1.69-1.62 (6H, m), 1.49 (2H, m), 1.02 (3H, t).

[4304] Eksperimentalni primer 1: Merenje aktivnosti GPR120 agonista (ispitivanje bazirano na ćelijama) [1644] CHO-K1 ćelije koje eksprimiraju Ga16 i hGPR120 su dispergovane u svaki bunarčić na ploči sa 96 bunarčića (3×10<4>ćelije/100 µℓ/bunarčić) a zatim su 18 sati inkubirani u 5% CO<2>, 37°C inkubatoru. Svaki bunarčić je tretiran sa 100 µℓ rastvora boje kalcijuma 5 (Molecular Devices) uključujući 2% DMSO a zatim je 1 sat inkubiran u 5% CO<2>, 37°C inkubatoru. Serijski razblaženi GPR120 agonisti su pripremljeni do konačne koncentracije od 0.5% DMSO u ploči sa 96 bunarčića. Svaki bunarčić je tretiran sa 50 µℓ jedinjenja agonista upotrbeom Plexstation II, a fluorescencija je merena na Ex 485 nm, Em 525 nm.[4304] Experimental Example 1: Measurement of GPR120 Agonist Activity (Cell-Based Assay) [1644] CHO-K1 cells expressing Ga16 and hGPR120 were dispersed into each well of a 96-well plate (3×10<4>cells/100 µℓ/well) and then incubated for 18 hours in 5% CO<2>, 37°C incubator. Each well was treated with 100 µℓ of calcium dye solution 5 (Molecular Devices) including 2% DMSO and then incubated for 1 hour in a 5% CO<2>, 37°C incubator. Serially diluted GPR120 agonists were prepared to a final concentration of 0.5% DMSO in a 96-well plate. Each well was treated with 50 µℓ of agonist compound using Plexstation II, and fluorescence was measured at Ex 485 nm, Em 525 nm.

[4305] Fluorescencija povećana serijskim rastvorenim GPR120 agonistima je računata kao vrednost relativnog procenta (%) bazirana na fluorescenciji koju predstavlja tretiranje od samo 1% DMSO. EC<50>se odnosi na koncentraciju agonista koja pokazuje 50% maksimalne fluorescencije povećane tretiranjem agonista. Računanje je izvedeno upotrebom statističkog softvera (Prizm).[4305] Fluorescence increased by serially dissolved GPR120 agonists was calculated as a relative percentage value (%) based on the fluorescence represented by treatment with 1% DMSO alone. EC<50> refers to the concentration of agonist that shows 50% of maximal fluorescence increased by agonist treatment. Calculations were performed using statistical software (Prizm).

[4306] Agonistički efekti primera jedinjenja dobijenog putem gore pomenutog eksperimenta su prikazani u tabeli 1 u nastavku sa EC<50>jedinicom (µM). Aktivnost je obeležena na osnovu sledećih kriterijuma:[4306] Agonistic effects of exemplary compounds obtained through the aforementioned experiment are shown in Table 1 below with EC<50>unit (µM). The activity is marked based on the following criteria:

[4307] A = >20 µM, B = 20∼2 µM, C = 2∼0.2 µM, D = <0.2 µM[4307] A = >20 µM, B = 20∼2 µM, C = 2∼0.2 µM, D = <0.2 µM

[4308] Kako je prikazano u tabeli, većina novih jedinjenja prema ovom pronalasku ima superiorne GPR120 agonističke efekte (EC<50>), manje od 0.2 µM.[4308] As shown in the table, most of the novel compounds of the present invention have superior GPR120 agonistic effects (EC<50>), less than 0.2 µM.

[4310] Tabela 1[4310] Table 1

[4312][4312]

[4313] [Tabela 1][4313] [Table 1]

[4316] [4316]

[4317] [4317]

[4318] [4318]

Claims (5)

1. Patentni zahtevi1. Patent claims 1. Biarilni derivat, ili njegova farmaceutski prihvatljiva so ili E- ili Z-izomer, ili R- ili S-izomer, odabran iz grupe koju čine sledeća jedinjenja:1. Biaryl derivative, or its pharmaceutically acceptable salt or E- or Z-isomer, or R- or S-isomer, selected from the group consisting of the following compounds: 4-[4-[6-(ciklobutoksi)-2-piridil]-2-(trifluorometil)fenoksi]buterna kiselina;4-[4-[6-(cyclobutoxy)-2-pyridyl]-2-(trifluoromethyl)phenoxy]butyric acid; 4-[[5-(2-ciklobutilsulfanil-3-piridil)-2-piridil]oksi]valerijanska kiselina;4-[[5-(2-cyclobutylsulfanyl-3-pyridyl)-2-pyridyl]oxy]valeric acid; 4-[2,6-difluoro-4-[6-(N-metilanilino)-2-piridil]fenoksi]buterna kiselina;4-[2,6-difluoro-4-[6-(N-methylanilino)-2-pyridyl]phenoxy]butyric acid; 4-{2,6-difluoro-4-[6-(2-metil-propenil)-piridin-2-il]-fenoksi}-buterna kiselina;4-{2,6-difluoro-4-[6-(2-methyl-propenyl)-pyridin-2-yl]-phenoxy}-butyric acid; 4-(4-{2-[3-(tert-butil-dimetil-silaniloksi)-ciklopentiloksi]-piridin-3-il}-2,6-difluorofenoksi)-buterna kiselina;4-(4-{2-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyloxy]-pyridin-3-yl}-2,6-difluorophenoxy)-butyric acid; 4-[4-(6-fenoksi-2-piridil)fenoksi]buterna kiselina;4-[4-(6-phenoxy-2-pyridyl)phenoxy]butyric acid; 4-[2,6-difluoro-4-(6-izopropilsulfanil-2-piridil)fenoksi]buterna kiselina;4-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]butyric acid; 4-[2,6-difluoro-4-(6-fenoksi-2-piridil)fenoksi]buterna kiselina;4-[2,6-difluoro-4-(6-phenoxy-2-pyridyl)phenoxy]butyric acid; 4-[2-hloro-4-(6-izopropilsulfanil-2-piridil)fenoksi]buterna kiselina;4-[2-chloro-4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]butyric acid; 4-[2-fluoro-4-(6-izopropilsulfanil-2-piridil)fenoksi]buterna kiselina;4-[2-fluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]butyric acid; 4-[4-(6-ciklopentilsulfanil-2-piridil)-2,6-difluoro-fenoksi]buterna kiselina;4-[4-(6-cyclopentylsulfanyl-2-pyridyl)-2,6-difluoro-phenoxy]butyric acid; 4-[4-(2-ciklobutilsulfanil-piridin-3-il)-2-metoksi-fenoksi]-buterna kiselina;4-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2-methoxy-phenoxy]-butyric acid; 4-[2,6-difluoro-4-(2-izopropilsulfanil-4-piridil)fenoksi]buterna kiselina;4-[2,6-difluoro-4-(2-isopropylsulfanyl-4-pyridyl)phenoxy]butyric acid; 4-[4-[6-(ciklopentoksi)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina;4-[4-[6-(cyclopentoxy)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid; 4-[4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-dimetil-fenoksi]-buterna kiselina;4-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-dimethyl-phenoxy]-butyric acid; 4-[4-[3-(ciklopentoksi)fenil]-2,6-difluoro-fenoksi]buterna kiselina;4-[4-[3-(cyclopentoxy)phenyl]-2,6-difluoro-phenoxy]butyric acid; 4-[2,6-difluoro-4-(6-pirolidin-1-il-2-piridil)fenoksi]buterna kiselina;4-[2,6-difluoro-4-(6-pyrrolidin-1-yl-2-pyridyl)phenoxy]butyric acid; 4-[4-(2-sec-butilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina4-[4-(2-sec-butylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid 4-[4-[3-(ciklopentoksi)fenil]-2,3-difluoro-fenoksi]buterna kiselina;4-[4-[3-(cyclopentoxy)phenyl]-2,3-difluoro-phenoxy]butyric acid; 4-[2,6-difluoro-4-[6-(1-piperidil)-2-piridil]fenoksi]buterna kiselina;4-[2,6-difluoro-4-[6-(1-piperidyl)-2-pyridyl]phenoxy]butyric acid; 4-[4-(6-anilino-2-piridil)-2,6-difluoro-fenoksi]buterna kiselina;4-[4-(6-anilino-2-pyridyl)-2,6-difluoro-phenoxy]butyric acid; 4-[4-[6-(ciklopentilamino)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina;4-[4-[6-(cyclopentylamino)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid; 4-[4-[6-(ciklopropilmetilsulfanil)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina;4-[4-[6-(cyclopropylmethylsulfanyl)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid; 4-[4-(6-ciklobutilsulfanil-2-piridil)-2,6-difluoro-fenoksi]buterna kiselina;4-[4-(6-cyclobutylsulfanyl-2-pyridyl)-2,6-difluoro-phenoxy]butyric acid; 4-[2,6-difluoro-4-(6-propilsulfanil-2-piridil)fenoksi]buterna kiselina;4-[2,6-difluoro-4-(6-propylsulfanyl-2-pyridyl)phenoxy]butyric acid; 4-[2,6-difluoro-4-(6-izopropoksi-2-piridil)fenoksi]buterna kiselina;4-[2,6-difluoro-4-(6-isopropoxy-2-pyridyl)phenoxy]butyric acid; 4-[2,6-difluoro-4-(6-propoksi-2-piridil)fenoksi]buterna kiselina;4-[2,6-difluoro-4-(6-propoxy-2-pyridyl)phenoxy]butyric acid; 4-[4-[6-(ciklopropilmetoksi)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina;4-[4-[6-(cyclopropylmethoxy)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid; 4-[4-[6-(ciklobutoksi)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina;4-[4-[6-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid; 4-[4-[6-(ciklobutoksi)-2-piridil]-2-metil-fenoksi]buterna kiselina;4-[4-[6-(cyclobutoxy)-2-pyridyl]-2-methyl-phenoxy]butyric acid; -[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]valerijanska kiselina;-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]valeric acid; -[4-[6-(ciklobutoksi)-2-piridil]-2,6-difluoro-fenoksi]valerijanska kiselina;-[4-[6-(cyclobutoxy)-2-pyridyl]-2,6-difluoro-phenoxy]valeric acid; -{2,6-difluoro-4-[2-(3-metil-butilsulfanil)-piridin-3-il]-fenoksi}-buterna kiselina-{2,6-difluoro-4-[2-(3-methyl-butylsulfanyl)-pyridin-3-yl]-phenoxy}-butyric acid -{2,6-difluoro-4-[2-(2-fluoro-etoksi)-piridin-3-il]-fenoksi}-buterna kiselina;-{2,6-difluoro-4-[2-(2-fluoro-ethoxy)-pyridin-3-yl]-phenoxy}-butyric acid; -[1-[[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]metil] ciklopropil]sirćetna kiselina; -[1-[[4-[3-(ciklobutoksi)fenil]-2,6-difluoro-fenoksi]metil]ciklopropil] sirćetna kiselina;-[1-[[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]methyl]cyclopropyl]acetic acid; -[1-[[4-[3-(cyclobutoxy)phenyl]-2,6-difluoro-phenoxy]methyl]cyclopropyl]acetic acid; -[[6-[3-(ciklobutoksi)fenil]-3-piridil]oksi]buterna kiselina;-[[6-[3-(cyclobutoxy)phenyl]-3-pyridyl]oxy]butyric acid; -[[6-[3-(ciklopentoksi)fenil]-3-piridil]oksi]buterna kiselina;-[[6-[3-(cyclopentoxy)phenyl]-3-pyridyl]oxy]butyric acid; -(2'-fenoksi-bifenil-4-iloksi)-buterna kiselina;-(2'-phenoxy-biphenyl-4-yloxy)-butyric acid; -[4-(2-izopropilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina;-[4-(2-isopropylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid; -(3,5-difluoro-2'-fenoksi-bifenil-4-iloksi)-buterna kiselina;-(3,5-difluoro-2'-phenoxy-biphenyl-4-yloxy)-butyric acid; -[4-(2-ciklopentilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina;-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid; -[2,6-difluoro-4-(2-izopropilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina;-[2,6-difluoro-4-(2-isopropylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid; -[2,6-difluoro-4-(2-fenoksi-piridin-3-il)-fenoksi]-buterna kiselina;-[2,6-difluoro-4-(2-phenoxy-pyridin-3-yl)-phenoxy]-butyric acid; -[2,6-difluoro-4-(2-izopropoksi-piridin-3-il)-fenoksi]-buterna kiselina;-[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenoxy]-butyric acid; -[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid; -[4-(2-ciklopentilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid; -[4-(2-ciklopropilmetoksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;-[4-(2-cyclopropylmethoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid; -[4-(2-ciklopropilmetilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid; -[4-(2-ciklobutilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina;-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid; -[4-(2-ciklopropilmetilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina;-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid; -[4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid; -[4-(2-propilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina;-[4-(2-propylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid; -(3,5-difluoro-2'-izopropoksi-bifenil-4-iloksi)-buterna kiselina;-(3,5-difluoro-2'-isopropoxy-biphenyl-4-yloxy)-butyric acid; -(2'-ciklobutoksi-3,5-difluoro-bifenil-4-iloksi)-buterna kiselina;-(2'-cyclobutoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric acid; -(2'-ciklopropilmetoksi-3,5-difluoro-bifenil-4-iloksi)-buterna kiselina;-(2'-cyclopropylmethoxy-3,5-difluoro-biphenyl-4-yloxy)-butyric acid; -(2'-ciklopentiloksi-3,5-difluoro-bifenil-4-iloksi)-buterna kiselina;-(2'-cyclopentyloxy-3,5-difluoro-biphenyl-4-yloxy)-butyric acid; -(2'-ciklopentiloksi-bifenil-4-iloksi)-buterna kiselina;-(2'-cyclopentyloxy-biphenyl-4-yloxy)-butyric acid; -(2'-izopropoksi-bifenil-4-iloksi)-buterna kiselina;-(2'-isopropoxy-biphenyl-4-yloxy)-butyric acid; -(2'-ciklopropilmetoksi-bifenil-4-iloksi)-buterna kiselina;-(2'-cyclopropylmethoxy-biphenyl-4-yloxy)-butyric acid; -[4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-2-metil-buterna kiselina;-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-2-methyl-butyric acid; -[4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-difluoro-fenoksimetil]-ciklopropankarboksilna kiselina; -[4-(2-ciklobutilsulfanil-piridin-3-il)-2,5-difluoro-fenoksi]-buterna kiselina;-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxymethyl]-cyclopropanecarboxylic acid; -[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,5-difluoro-phenoxy]-butyric acid; -[4-(6-ciklobutilsulfanil-piridin-2-il)-2,5-difluoro-fenoksi]-buterna kiselina;-[4-(6-cyclobutylsulfanyl-pyridin-2-yl)-2,5-difluoro-phenoxy]-butyric acid; -[4-(2-tert-butilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;-[4-(2-tert-butylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid; -[2,6-difluoro-4-(2-propilsulfanil-3-piridil)fenoksi]kapronska kiselina; -[2,6-difluoro-4-(6-izobutil-piridin-2-il)-fenoksi]-buterna kiselina;-[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)phenoxy]caproic acid; -[2,6-difluoro-4-(6-isobutyl-pyridin-2-yl)-phenoxy]-butyric acid; -[4-(2-ciklobutilsulfanil-piridin-3-il)-3,5-difluoro-fenoksi]-buterna kiselina;-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-3,5-difluoro-phenoxy]-butyric acid; -{2,6-difluoro-4-[2-(tetrahidro-piran-4-iloksi)-piridin-3-il]-fenoksi}-buterna kiselina; -{2,6-difluoro-4-[2-(tetrahidro-furan-3-iloksi)-piridin-3-il]-fenoksi}-buterna kiselina; -[4-(2-ciklobutoksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;-{2,6-difluoro-4-[2-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-phenoxy}-butyric acid; -{2,6-difluoro-4-[2-(tetrahydro-furan-3-yloxy)-pyridin-3-yl]-phenoxy}-butyric acid; -[4-(2-cyclobutoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid; -{2,6-difluoro-4-[2-(2-metoksi-etoksi)-piridin-3-il]-fenoksi}-buterna kiselina;-{2,6-difluoro-4-[2-(2-methoxy-ethoxy)-pyridin-3-yl]-phenoxy}-butyric acid; -[2,6-difluoro-4-(2-pirolidin-1-il-3-piridil)fenoksi]buterna kiselina;-[2,6-difluoro-4-(2-pyrrolidin-1-yl-3-pyridyl)phenoxy]butyric acid; -[4-[2-(ciklopentilamino)-3-piridil]-2,6-difluoro-fenoksi]buterna kiselina;-[4-[2-(cyclopentylamino)-3-pyridyl]-2,6-difluoro-phenoxy]butyric acid; -[4-[2-(ciklopropilmetilamino)-3-piridil]-2,6-difluoro-fenoksi]buterna kiselina; -[4-[6-(ciklopropilmetilamino)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina; -[2,6-difluoro-4-[2-(izopropilamino)-3-piridil]fenoksi]buterna kiselina;-[4-[2-(cyclopropylmethylamino)-3-pyridyl]-2,6-difluoro-phenoxy]butyric acid; -[4-[6-(cyclopropylmethylamino)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid; -[2,6-difluoro-4-[2-(isopropylamino)-3-pyridyl]phenoxy]butyric acid; -[4-[2-(ciklopropilamino)-3-piridil]-2,6-difluoro-fenoksi]buterna kiselina;-[4-[2-(cyclopropylamino)-3-pyridyl]-2,6-difluoro-phenoxy]butyric acid; -[2,6-difluoro-4-[6-(izopropilamino)-2-piridil]fenoksi]buterna kiselina;-[2,6-difluoro-4-[6-(isopropylamino)-2-pyridyl]phenoxy]butyric acid; -[4-[2-(ciklopentilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina;-[4-[2-(cyclopentylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid; -[4-[3-(ciklopentilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina;-[4-[3-(cyclopentylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid; -[2,6-difluoro-4-[2-(propilamino)fenil]fenoksi]buterna kiselina;-[2,6-difluoro-4-[2-(propylamino)phenyl]phenoxy]butyric acid; -[4-[2-(ciklopropilmetilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina;-[4-[2-(cyclopropylmethylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid; -[2,6-difluoro-4-[2-(izopropilamino)fenil]fenoksi]buterna kiselina;-[2,6-difluoro-4-[2-(isopropylamino)phenyl]phenoxy]butyric acid; -[4-[2-(ciklopentilamino)fenil]fenoksi]buterna kiselina;-[4-[2-(cyclopentylamino)phenyl]phenoxy]butyric acid; -[4-[2-(ciklopropilmetilamino)fenil]fenoksi]buterna kiselina;-[4-[2-(cyclopropylmethylamino)phenyl]phenoxy]butyric acid; -[4-[2-(propilamino)fenil]fenoksi]buterna kiselina;-[4-[2-(propylamino)phenyl]phenoxy]butyric acid; -[4-[2-(izopropilamino)fenil]fenoksi]buterna kiselina;-[4-[2-(isopropylamino)phenyl]phenoxy]butyric acid; -[4-[2-(ciklobutilamino)fenil]fenoksi]buterna kiselina;-[4-[2-(cyclobutylamino)phenyl]phenoxy]butyric acid; -[4-[2-(ciklobutilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina;-[4-[2-(cyclobutylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid; -[4-[3-(ciklopropilmetilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina;-[4-[3-(cyclopropylmethylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid; -[2,6-difluoro-4-[3-(izopropilamino)fenil]fenoksi]buterna kiselina;-[2,6-difluoro-4-[3-(isopropylamino)phenyl]phenoxy]butyric acid; -[2,6-difluoro-4-(3-pirolidin-1-ilfenil)fenoksi]buterna kiselina;-[2,6-difluoro-4-(3-pyrrolidin-1-ylphenyl)phenoxy]butyric acid; -[4-[3-(ciklobutilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina;-[4-[3-(cyclobutylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid; -[2,6-difluoro-4-[3-(propilamino)fenil]fenoksi]buterna kiselina;-[2,6-difluoro-4-[3-(propylamino)phenyl]phenoxy]butyric acid; -[4-[5-hloro-2-(ciklopentilamino)fenil]-2,6-difluoro-fenoksi]buterna kiselina;-[4-[5-chloro-2-(cyclopentylamino)phenyl]-2,6-difluoro-phenoxy]butyric acid; -[4-[2-(ciklopentilamino)-5-fluoro-fenil]-2,6-difluoro-fenoksi]buterna kiselina; -[4-(3-ciklopentilfenil)-2,6-difluoro-fenoksi]buterna kiselina;-[4-[2-(cyclopentylamino)-5-fluoro-phenyl]-2,6-difluoro-phenoxy]butyric acid; -[4-(3-cyclopentylphenyl)-2,6-difluoro-phenoxy]butyric acid; -[4-[3-(ciklopentilmetil)fenil]-2,6-difluoro-fenoksi]buterna kiselina;-[4-[3-(cyclopentylmethyl)phenyl]-2,6-difluoro-phenoxy]butyric acid; -[4-[2-(ciklopentilmetil)fenil]-2,6-difluoro-fenoksi]buterna kiselina;-[4-[2-(cyclopentylmethyl)phenyl]-2,6-difluoro-phenoxy]butyric acid; -[4-[6-(ciklopentilmetil)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina;-[4-[6-(cyclopentylmethyl)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid; -[4-[2-(ciklobutilmetil)fenil]-2,6-difluoro-fenoksi]buterna kiselina; 4-[4-[3-(ciklobutilmetil)fenil]-2,6-difluoro-fenoksi]buterna kiselina;-[4-[2-(cyclobutylmethyl)phenyl]-2,6-difluoro-phenoxy]butyric acid; 4-[4-[3-(cyclobutylmethyl)phenyl]-2,6-difluoro-phenoxy]butyric acid; 4-[4-[6-(ciklobutilmetil)-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina;4-[4-[6-(cyclobutylmethyl)-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid; 4-[4-(2-ciklopentilfenil)-2,6-difluoro-fenoksi]buterna kiselina;4-[4-(2-cyclopentylphenyl)-2,6-difluoro-phenoxy]butyric acid; 4-[4-(6-ciklopentil-2-piridil)-2,6-difluoro-fenoksi]buterna kiselina;4-[4-(6-cyclopentyl-2-pyridyl)-2,6-difluoro-phenoxy]butyric acid; 4-[2,6-difluoro-4-(2-izobutil-3-piridil)fenoksi]buterna kiselina;4-[2,6-difluoro-4-(2-isobutyl-3-pyridyl)phenoxy]butyric acid; 4-[4-(2-ciklopentil-3-piridil)-2,6-difluoro-fenoksi]buterna kiselina;4-[4-(2-cyclopentyl-3-pyridyl)-2,6-difluoro-phenoxy]butyric acid; 4-[4-[2-(ciklopentilmetil)-3-piridil]-2,6-difluoro-fenoksi]buterna kiselina;4-[4-[2-(cyclopentylmethyl)-3-pyridyl]-2,6-difluoro-phenoxy]butyric acid; 4-[2,6-difluoro-4-(2-pirol-1-il-3-piridil)fenoksi]buterna kiselina;4-[2,6-difluoro-4-(2-pyrrol-1-yl-3-pyridyl)phenoxy]butyric acid; 4-[2,6-difluoro-4-[2-(4-metilpirazol-1-il)-3-piridil]fenoksi]buterna kiselina;4-[2,6-difluoro-4-[2-(4-methylpyrazol-1-yl)-3-pyridyl]phenoxy]butyric acid; 4-[2,6-difluoro-4-(2-morfolino-3-piridil)fenoksi]buterna kiselina;4-[2,6-difluoro-4-(2-morpholino-3-pyridyl)phenoxy]butyric acid; 4-[2,6-difluoro-4-[2-(tetrahidropiran-4-ilmetilamino)-3-piridil]fenoksi] buterna kiselina; 4-[2,6-difluoro-4-[2-(1-piperidil)-3-piridil]fenoksi]buterna kiselina;4-[2,6-difluoro-4-[2-(tetrahydropyran-4-ylmethylamino)-3-pyridyl]phenoxy]butyric acid; 4-[2,6-difluoro-4-[2-(1-piperidyl)-3-pyridyl]phenoxy]butyric acid; (4S)-4-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]valerijanska kiselina;(4S)-4-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]valeric acid; (4R)-4-[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]valerijanska kiselina;(4R)-4-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]valeric acid; (4R)-4-[4-[3-(ciklobutoksi)fenil]-2,6-difluoro-fenoksi]valerijanska kiselina;(4R)-4-[4-[3-(cyclobutoxy)phenyl]-2,6-difluoro-phenoxy]valeric acid; (4R)-4-[4-(2-ciklopentilsulfanil-3-piridil)-2,6-difluoro-fenoksi]valerijanska kiselina; (4R)-4-[2,6-difluoro-4-(3-fenoksifenil)fenoksi]valerijanska kiselina;(4R)-4-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]valeric acid; (4R)-4-[2,6-difluoro-4-(3-phenoxyphenyl)phenoxy]valeric acid; 4-(3'-ciklobutoksi-bifenil-4-ilsulfanil)-buterna kiselina;4-(3'-cyclobutoxy-biphenyl-4-ylsulfanyl)-butyric acid; 4-(3'-izopropoksi-bifenil-4-ilsulfanil)-buterna kiselina;4-(3'-isopropoxy-biphenyl-4-ylsulfanyl)-butyric acid; [1-(3,5-difluoro-3'-izopropoksi-bifenil-4-ilsulfanilmetil)-ciklopropil]-sirćetna kiselina; 4-(3'-ciklopentiloksi-3,5-difluoro-bifenil-4-ilsulfanil)-buterna kiselina;[1-(3,5-difluoro-3'-isopropoxy-biphenyl-4-ylsulfanylmethyl)-cyclopropyl]-acetic acid; 4-(3'-cyclopentyloxy-3,5-difluoro-biphenyl-4-ylsulfanyl)-butyric acid; 4-[4-(2-ciklopentiloksi-piridin-3-il)-fenilsulfanil]-buterna kiselina;4-[4-(2-cyclopentyloxy-pyridin-3-yl)-phenylsulfanyl]-butyric acid; 4-[4-(2-ciklopropilmetoksi-piridin-3-il)-fenilsulfanil]-buterna kiselina;4-[4-(2-cyclopropylmethoxy-pyridin-3-yl)-phenylsulfanyl]-butyric acid; 4-(3'-fenoksi-bifenil-4-ilsulfanil)-buterna kiselina;4-(3'-phenoxy-biphenyl-4-ylsulfanyl)-butyric acid; 4-(3'-ciklopentiloksi-bifenil-4-ilsulfanil)-buterna kiselina;4-(3'-cyclopentyloxy-biphenyl-4-ylsulfanyl)-butyric acid; 4-(3'-propoksi-bifenil-4-ilsulfanil)-buterna kiselina;4-(3'-propoxy-biphenyl-4-ylsulfanyl)-butyric acid; 4-[4-(6-ciklobutoksi-piridin-2-il)-fenilsulfanil]-buterna kiselina;4-[4-(6-cyclobutoxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid; 4-[4-(6-ciklopentiloksi-piridin-2-il)-fenilsulfanil]-buterna kiselina;4-[4-(6-cyclopentyloxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid; 4-[4-(6-izopropoksi-piridin-2-il)-fenilsulfanil]-buterna kiselina;4-[4-(6-isopropoxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid; 4-[4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-buterna kiselina;4-[4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-butyric acid; 4-[4-(6-propoksi-piridin-2-il)-fenilsulfanil]-buterna kiselina;4-[4-(6-propoxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid; 4-[4-(6-ciklopentilsulfanil-piridin-2-il)-fenilsulfanil]-buterna kiselina;4-[4-(6-cyclopentylsulfanyl-pyridin-2-yl)-phenylsulfanyl]-butyric acid; 4-(3'-ciklobutoksi-3,5-difluoro-bifenil-4-ilsulfanil)-buterna kiselina;4-(3'-cyclobutoxy-3,5-difluoro-biphenyl-4-ylsulfanyl)-butyric acid; 4-(3,5-difluoro-3'-izopropoksi-bifenil-4-ilsulfanil)-buterna kiselina;4-(3,5-difluoro-3'-isopropoxy-biphenyl-4-ylsulfanyl)-butyric acid; 4-[2,6-difluoro-4-(6-propoksi-piridin-2-il)-fenilsulfanil]-buterna kiselina;4-[2,6-difluoro-4-(6-propoxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid; 4-[2,6-difluoro-4-(6-izopropoksi-piridin-2-il)-fenilsulfanil]-buterna kiselina; -[2,6-difluoro-4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-buterna kiselina;4-[2,6-difluoro-4-(6-isopropoxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid; -[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-butyric acid; -[2,6-difluoro-4-(2-propoksi-piridin-3-il)-fenilsulfanil]-buterna kiselina;-[2,6-difluoro-4-(2-propoxy-pyridin-3-yl)-phenylsulfanyl]-butyric acid; -[2,6-difluoro-4-(6-izopropilsulfanil-piridin-2-il)-fenilsulfanil]-buterna kiselina; -[2,6-difluoro-4-(6-propilsulfanil-piridin-2-il)-fenilsulfanil]-buterna kiselina; -[4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina; -[4-(2-ciklobutoksi-piridin-3-il)-fenilsulfanil]-buterna kiselina;-[2,6-difluoro-4-(6-isopropylsulfanyl-pyridin-2-yl)-phenylsulfanyl]-butyric acid; -[2,6-difluoro-4-(6-propylsulfanyl-pyridin-2-yl)-phenylsulfanyl]-butyric acid; -[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid; -[4-(2-cyclobutoxy-pyridin-3-yl)-phenylsulfanyl]-butyric acid; -[4-(2-ciklobutoksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina;-[4-(2-cyclobutoxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid; -[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina; -[2,6-difluoro-4-(2-izopropilsulfanil-piridin-3-il)-fenilsulfanil]-buterna kiselina; -[4-(2-ciklopentilsulfanil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina; -[4-(2-izopropilsulfanil-piridin-3-il)-fenilsulfanil]-buterna kiselina;-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid; -[2,6-difluoro-4-(2-isopropylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-butyric acid; -[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid; -[4-(2-isopropylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-butyric acid; -[4-(2-ciklopentilsulfanil-piridin-3-il)-fenilsulfanil]-buterna kiselina;-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-butyric acid; -[2-fluoro-4-(6-izopropoksi-piridin-2-il)-fenilsulfanil]-buterna kiselina;-[2-fluoro-4-(6-isopropoxy-pyridin-2-yl)-phenylsulfanyl]-butyric acid; -[4-(2-ciklopentiloksi-piridin-3-il)-2-fluoro-fenilsulfanil]-buterna kiselina;-[4-(2-cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric acid; -[4-(2-ciklobutilsulfanil-piridin-3-il)-2-fluoro-fenilsulfanil]-buterna kiselina; -[4-(2-ciklobutilsulfanil-piridin-3-il)-fenilsulfanil]-buterna kiselina;-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric acid; -[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-butyric acid; -[4-(6-ciklobutoksi-piridin-2-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina;-[4-(6-cyclobutoxy-pyridin-2-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid; -[4-(6-ciklopentiloksi-piridin-2-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina; -[4-(6-ciklobutilsulfanil-piridin-2-il)-fenilsulfanil]-buterna kiselina;-[4-(6-cyclopentyloxy-pyridin-2-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid; -[4-(6-cyclobutylsulfanyl-pyridin-2-yl)-phenylsulfanyl]-butyric acid; -[4-(6-ciklopropilmetoksi-piridin-2-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina; -[4-(6-ciklobutilsulfanil-piridin-2-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina; -[4-(6-ciklopentilsulfanil-piridin-2-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina; -(2'-ciklopentilamino-3-fluoro-bifenil-4-ilsulfanil)-buterna kiselina;-[4-(6-cyclopropylmethoxy-pyridin-2-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid; -[4-(6-cyclobutylsulfanyl-pyridin-2-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid; -[4-(6-cyclopentylsulfanyl-pyridin-2-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid; -(2'-cyclopentylamino-3-fluoro-biphenyl-4-ylsulfanyl)-butyric acid; -(2'-ciklopentilamino-3,5-difluoro-bifenil-4-ilsulfanil)-buterna kiselina;-(2'-cyclopentylamino-3,5-difluoro-biphenyl-4-ylsulfanyl)-butyric acid; -[2'-(ciklopropilmetil-amino)-3,5-difluoro-bifenil-4-ilsulfanil]-buterna kiselina; -[2-fluoro-4-(2-izopropilsulfanil-piridin-3-il)-fenilsulfanil]-buterna kiselina; -[4-(2-ciklopentilsulfanil-piridin-3-il)-2-fluoro-fenilsulfanil]-buterna kiselina; -(3,5-difluoro-2'-izopropilamino-bifenil-4-ilsulfanil)-buterna kiselina;-[2'-(cyclopropylmethyl-amino)-3,5-difluoro-biphenyl-4-ylsulfanyl]-butyric acid; -[2-fluoro-4-(2-isopropylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-butyric acid; -[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric acid; -(3,5-difluoro-2'-isopropylamino-biphenyl-4-ylsulfanyl)-butyric acid; -(3,5-difluoro-2'-propilamino-bifenil-4-ilsulfanil)-buterna kiselina;-(3,5-difluoro-2'-propylamino-biphenyl-4-ylsulfanyl)-butyric acid; -[4-(2-ciklopropilmetoksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina; -[2,6-difluoro-4-(2-propilsulfanil-piridin-3-il)-fenilsulfanil]-buterna kiselina; -[4-(6-ciklobutilsulfanil-piridin-2-il)-2-fluoro-fenilsulfanil]-buterna kiselina; -[4-(2-ciklopentilamino-piridin-3-il)-2-fluoro-fenilsulfanil]-buterna kiselina; -[2-fluoro-4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-buterna kiselina;-[4-(2-cyclopropylmethoxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid; -[2,6-difluoro-4-(2-propylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-butyric acid; -[4-(6-cyclobutylsulfanyl-pyridin-2-yl)-2-fluoro-phenylsulfanyl]-butyric acid; -[4-(2-cyclopentylamino-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric acid; -[2-fluoro-4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-butyric acid; -[4-(2-ciklobutoksi-piridin-3-il)-2-fluoro-fenilsulfanil]-buterna kiselina;-[4-(2-cyclobutoxy-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric acid; -[2-fluoro-4-(2-pirolidin-1-il-piridin-3-il)-fenilsulfanil]-buterna kiselina; -[2-fluoro-4-(2-izopropilamino-piridin-3-il)-fenilsulfanil]-buterna kiselina;-[2-fluoro-4-(2-pyrrolidin-1-yl-pyridin-3-yl)-phenylsulfanyl]-butyric acid; -[2-fluoro-4-(2-isopropylamino-pyridin-3-yl)-phenylsulfanyl]-butyric acid; -(2'-ciklopentilamino-3,5'-difluoro-bifenil-4-ilsulfanil)-buterna kiselina;-(2'-cyclopentylamino-3,5'-difluoro-biphenyl-4-ylsulfanyl)-butyric acid; -(2'-ciklopentilamino-5'-fluoro-bifenil-4-ilsulfanil)-buterna kiselina;-(2'-cyclopentylamino-5'-fluoro-biphenyl-4-ylsulfanyl)-butyric acid; -(2'-ciklopentiloksi-5'-metil-bifenil-4-ilsulfanil)-buterna kiselina;-(2'-cyclopentyloxy-5'-methyl-biphenyl-4-ylsulfanyl)-butyric acid; -(2'-ciklopentiloksi-4'-metoksi-bifenil-4-ilsulfanil)-buterna kiselina;-(2'-cyclopentyloxy-4'-methoxy-biphenyl-4-ylsulfanyl)-butyric acid; -(2'-ciklopentiloksi-5'-fluoro-bifenil-4-ilsulfanil)-buterna kiselina;-(2'-cyclopentyloxy-5'-fluoro-biphenyl-4-ylsulfanyl)-butyric acid; -(2'-ciklopentiloksi-3,5'-difluoro-bifenil-4-ilsulfanil)-buterna kiselina;-(2'-cyclopentyloxy-3,5'-difluoro-biphenyl-4-ylsulfanyl)-butyric acid; -[4-(2-ciklopentiloksi-5-metil-piridin-3-il)-fenilsulfanil]-buterna kiselina;-[4-(2-cyclopentyloxy-5-methyl-pyridin-3-yl)-phenylsulfanyl]-butyric acid; -(2'-ciklopentiloksi-3,5,5'-trifluoro-bifenil-4-ilsulfanil)-buterna kiselina;-(2'-cyclopentyloxy-3,5,5'-trifluoro-biphenyl-4-ylsulfanyl)-butyric acid; -(2'-ciklopentiloksi-3-fluoro-4'-metoksi-bifenil-4-ilsulfanil)-buterna kiselina;-(2'-cyclopentyloxy-3-fluoro-4'-methoxy-biphenyl-4-ylsulfanyl)-butyric acid; -(2'-ciklopentiloksi-3,5-difluoro-4'-metoksi-bifenil-4-ilsulfanil)-buterna kiselina; -(3-fluoro-2'-izopropoksi-4'-metoksi-bifenil-4-ilsulfanil)-buterna kiselina;-(2'-cyclopentyloxy-3,5-difluoro-4'-methoxy-biphenyl-4-ylsulfanyl)-butyric acid; -(3-fluoro-2'-isopropoxy-4'-methoxy-biphenyl-4-ylsulfanyl)-butyric acid; -[4-(2-ciklopentiloksi-5-metil-piridin-3-il)-2-fluoro-fenilsulfanil]-buterna kiselina; -[2-fluoro-4-(2-izopropoksi-5-metil-piridin-3-il)-fenilsulfanil]-buterna kiselina;-[4-(2-cyclopentyloxy-5-methyl-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric acid; -[2-fluoro-4-(2-isopropoxy-5-methyl-pyridin-3-yl)-phenylsulfanyl]-butyric acid; -(3,5'-difluoro-2'-izopropoksi-bifenil-4-iisulfanil)-buterna kiselina;-(3,5'-difluoro-2'-isopropoxy-biphenyl-4-isosulfanyl)-butyric acid; -[4-(2-ciklopentiloksi-6-metil-piridin-3-il)-2-fluoro-fenilsulfanil]-buterna kiselina; -(3,3'-difluoro-2'-izopropoksi-5'-metil-bifenil-4-ilsulfanil)-buterna kiselina;-[4-(2-cyclopentyloxy-6-methyl-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric acid; -(3,3'-difluoro-2'-isopropoxy-5'-methyl-biphenyl-4-ylsulfanyl)-butyric acid; -(3,3'-difluoro-5'-metil-2'-propoksi-bifenil-4-ilsulfanil)-buterna kiselina;-(3,3'-difluoro-5'-methyl-2'-propoxy-biphenyl-4-ylsulfanyl)-butyric acid; -(3-fluoro-2',4'-dipropoksi-bifenil-4-ilsulfanil)-buterna kiselina;-(3-fluoro-2',4'-dipropoxy-biphenyl-4-ylsulfanyl)-butyric acid; -(6'-ciklopentiloksi-3,2'-difluoro-3'-metil-bifenil-4-ilsulfanil)-buterna kiselina;-(6'-cyclopentyloxy-3,2'-difluoro-3'-methyl-biphenyl-4-ylsulfanyl)-butyric acid; -(2'-ciklopentiloksi-3,3'-difluoro-bifenil-4-ilsulfanil)-buterna kiselina;-(2'-cyclopentyloxy-3,3'-difluoro-biphenyl-4-ylsulfanyl)-butyric acid; -(2'-ciklopentiloksi-3,3'-difluoro-5'-metil-bifenil-4-ilsulfanil)-buterna kiselina;-(2'-cyclopentyloxy-3,3'-difluoro-5'-methyl-biphenyl-4-ylsulfanyl)-butyric acid; -[4-(2-ciklobutilmetoksi-piridin-3-il)-2,6-difluoro-fenoksi]-valerijanska kiselina; -[4-(2-ciklopropoksi-piridin-3-il)-2,6-difluoro-fenoksi]-valerijanska kiselina;-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-valeric acid; -[4-(2-cyclopropoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-valeric acid; -[4-(2-ciklopentiloksi-5-metil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina; -[4-(2-ciklopentiloksi-piridin-3-il)-fenilsulfanil]-valerijanska kiselina;-[4-(2-cyclopentyloxy-5-methyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid; -[4-(2-cyclopentyloxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid; -[4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-valerijanska kiselina;-[4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid; -[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-valerijanska kiselina; -[4-(2-ciklopentilsulfanil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-valerijanska kiselina; -[4-[2-(2-dimetilaminoetiloksi)-3-piridil]-2,6-difluoro-fenoksi]buterna kiselina; -[2,6-difluoro-4-(2-propilsulfanil-piridin-3-il)-fenoksi]-buterna kiselina;-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-valeric acid; -[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-valeric acid; -[4-[2-(2-dimethylaminoethyloxy)-3-pyridyl]-2,6-difluoro-phenoxy]butyric acid; -[2,6-difluoro-4-(2-propylsulfanyl-pyridin-3-yl)-phenoxy]-butyric acid; -[4-(2-ciklopropilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;-[4-(2-cyclopropylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid; -[4-(2-etilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;-[4-(2-ethylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid; -[4-(2-butilsulfanil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;-[4-(2-butylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid; -(2'-ciklopentilamino-bifenil-4-ilsulfanil)-buterna kiselina;-(2'-cyclopentylamino-biphenyl-4-ylsulfanyl)-butyric acid; -[4-(2-ciklopentiloksi-5-metil-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina; -[4-(6-izopropilsulfanil-2-piridil)fenoksi]buterna kiselina;-[4-(2-cyclopentyloxy-5-methyl-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid; -[4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]butyric acid; -[2,6-difluoro-4-(3-fenoksifenil)fenoksi]buterna kiselina;-[2,6-difluoro-4-(3-phenoxyphenyl)phenoxy]butyric acid; -[4-[6-[3-(dimetilamino)pirolidin-1-il]-2-piridil]-2,6-difluoro-fenoksi]buterna kiselina; -[2,6-difluoro-4-(2-izopropoksi-piridin-3-il)-fenoksi]-valerijanska kiselina-[4-[6-[3-(dimethylamino)pyrrolidin-1-yl]-2-pyridyl]-2,6-difluoro-phenoxy]butyric acid; -[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenoxy]-valeric acid -[4-(2-ciklobutoksi-piridin-3-il)-2,6-difluoro-fenoksi]-valerijanska kiselina-[4-(2-cyclobutoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-valeric acid -[4-[2-(3,3-difluoropirolidin-1-il)-3-piridil]-2,6-difluoro-fenoksi]buterna kiselina; -[2,6-difluoro-4-[2-(4-metilpiperazin-1-il)-3-piridil]fenoksi]buterna kiselina;-[4-[2-(3,3-difluoropyrrolidin-1-yl)-3-pyridyl]-2,6-difluoro-phenoxy]butyric acid; -[2,6-difluoro-4-[2-(4-methylpiperazin-1-yl)-3-pyridyl]phenoxy]butyric acid; -[2,6-difluoro-4-[2-(5-metilisoksazol-3-il)oksi-3-piridil]fenoksi]buterna kiselina; -[4-[2-[2-(aziridin-1-il)etoksi]-3-piridil]-2,6-difluoro-fenoksi]buterna kiselina;-[2,6-difluoro-4-[2-(5-methylisoxazol-3-yl)oxy-3-pyridyl]phenoxy]butyric acid; -[4-[2-[2-(aziridin-1-yl)ethoxy]-3-pyridyl]-2,6-difluoro-phenoxy]butyric acid; -[2,6-difluoro-4-[2-(furilmetoksi)-3-piridil]fenoksi]buterna kiselina;-[2,6-difluoro-4-[2-(furylmethoxy)-3-pyridyl]phenoxy]butyric acid; -[2,6-difluoro-4-[2-(2-furilmetoksi)-3-piridil]fenoksi]buterna kiselina;-[2,6-difluoro-4-[2-(2-furylmethoxy)-3-pyridyl]phenoxy]butyric acid; -[2,6-difluoro-4-[2-[(3-metiloksetan-3-il)metoksi]-3-piridil]fenoksi] buterna kiselina; -[2,6-difluoro-4-[2-(tetrahidrofuran-3-ilmetoksi)-3-piridil]fenoksi] buterna kiselina; -[2,6-difluoro-4-[2-(tetrahidrofuran-2-ilmetoksi)-3-piridil]fenoksi] buterna kiselina; -[4-(2-ciklobutilmetoksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;-[2,6-difluoro-4-[2-[(3-methyloxetan-3-yl)methoxy]-3-pyridyl]phenoxy] butyric acid; -[2,6-difluoro-4-[2-(tetrahydrofuran-3-ylmethoxy)-3-pyridyl]phenoxy] butyric acid; -[2,6-difluoro-4-[2-(tetrahydrofuran-2-ylmethoxy)-3-pyridyl]phenoxy]butyric acid; -[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid; -[4-(2-ciklopropoksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;-[4-(2-cyclopropoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid; -{2,6-difluoro-4-[2-(3-hidroksi-ciklopentiloksi)-piridin-3-il]-fenoksi}-buterna kiselina; -[4-(2-cikloheksiloksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;-{2,6-difluoro-4-[2-(3-hydroxy-cyclopentyloxy)-pyridin-3-yl]-phenoxy}-butyric acid; -[4-(2-cyclohexyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid; -[4-(2-ciklopentilmetoksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;-[4-(2-cyclopentylmethoxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid; -[2,6-difluoro-4-(2-isobutoksi-piridin-3-il)-fenoksi]-buterna kiselina;-[2,6-difluoro-4-(2-isobutoxy-pyridin-3-yl)-phenoxy]-butyric acid; -{4-[2-(2,2-dimeti-propoksi)-piridin-3-il]-2,6-difluoro-fenoksi}-buterna kiselina; -[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenoksi]-valerijanska kiselina;-{4-[2-(2,2-dimethyl-propoxy)-pyridin-3-yl]-2,6-difluoro-phenoxy}-butyric acid; -[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-valeric acid; -[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]valerijanska kiselina;-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]valeric acid; -[4-(2-ciklopentilsulfanil-3-piridil)-2,6-difluoro-fenoksi]valerijanska kiselina;-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]valeric acid; -[2,6-difluoro-4-(2-izopropilsulfanil-3-piridil)fenoksi]valerijanska kiselina;-[2,6-difluoro-4-(2-isopropylsulfanyl-3-pyridyl)phenoxy]valeric acid; -[2,6-difluoro-4-(2-propilsulfanil-3-piridil)fenoksi]valerijanska kiselina;-[2,6-difluoro-4-(2-propylsulfanyl-3-pyridyl)phenoxy]valeric acid; -[2,6-difluoro-4-(6-izopropilsulfanil-2-piridil)fenoksi]valerijanska kiselina;-[2,6-difluoro-4-(6-isopropylsulfanyl-2-pyridyl)phenoxy]valeric acid; -[2,6-difluoro-4-(6-izopropoksi-2-piridil)fenoksi]valerijanska kiselina;-[2,6-difluoro-4-(6-isopropoxy-2-pyridyl)phenoxy]valeric acid; -[4-[2-(ciklopropilmetoksi)-3-piridil]-2,6-difluoro-fenoksi]valerijanska kiselina;-[4-[2-(cyclopropylmethoxy)-3-pyridyl]-2,6-difluoro-phenoxy]valeric acid; -[2,6-difluoro-4-(2-tetrahidrofuran-3-iloksi-3-piridil)fenoksi]valerijanska kiselina; -[2,6-difluoro-4-(2-tetrahidropiran-4-iloksi-3-piridil)fenoksi]valerijanska kiselina; -[2,6-difluoro-4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-valerijanska kiselina;-[2,6-difluoro-4-(2-tetrahydrofuran-3-yloxy-3-pyridyl)phenoxy]valeric acid; -[2,6-difluoro-4-(2-tetrahydropyran-4-yloxy-3-pyridyl)phenoxy]valeric acid; -[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid; -[4-(2-ciklopentilsulfanil-piridin-3-il)-fenilsulfanil]-valerijanska kiselina;-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-valeric acid; -{2-fluoro-4-[2-(tetrahidro-piran-4-iloksi)-piridin-3-il]-fenilsulfanil}-buterna kiselina; -{2-fluoro-4-[2-(tetrahidrofuran-3-iloksi)-piridin-3-il]-fenilsulfanil}-buterna kiselina; -[4-(2-ciklobutilmetoksi-piridin-3-il)-2-fluoro-fenilsulfanil]-buterna kiselina; -{2,6-difluoro-4-[2-(2,2,2-trifluoro-etoksi)-piridin-3-il]-fenilsulfanil}-buterna kiselina; -[4-(2-ciklobutilmetoksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina;-{2-fluoro-4-[2-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-phenylsulfanyl}-butyric acid; -{2-fluoro-4-[2-(tetrahydrofuran-3-yloxy)-pyridin-3-yl]-phenylsulfanyl}-butyric acid; -[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2-fluoro-phenylsulfanyl]-butyric acid; -{2,6-difluoro-4-[2-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-phenylsulfanyl}-butyric acid; -[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid; -[4-(2-ciklopentilamino-piridin-3-il)-2,6-difluoro-fenilsulfanil]-buterna kiselina;-[4-(2-cyclopentylamino-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-butyric acid; -[2,6-difluoro-4-(2-izopropilamino-piridin-3-il)-fenilsulfanil]-buterna kiselina;-[2,6-difluoro-4-(2-isopropylamino-pyridin-3-yl)-phenylsulfanyl]-butyric acid; -{4-[2-(ciklopropilmetil-amino)-piridin-3-il]-2,6-difluoro-fenilsulfanil}-buterna kiselina; -[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-valerijanska kiselina; -[2,6-difluoro-4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-valerijanska kiselina;-{4-[2-(cyclopropylmethyl-amino)-pyridin-3-yl]-2,6-difluoro-phenylsulfanyl}-butyric acid; -[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-valeric acid; -[2,6-difluoro-4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid; -[4-(2-ciklopentiloksi-piridin-3-il)-fenilsulfanil]-valerijanska kiselina;-[4-(2-cyclopentyloxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid; -[4-(2-izopropoksi-piridin-3-il)-fenilsulfanil]-valerijanska kiselina;-[4-(2-isopropoxy-pyridin-3-yl)-phenylsulfanyl]-valeric acid; -[4-(2-ciklopentilsulfanil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-valerijanska kiselina; -[2,6-difluoro-4-(2-propilsulfanil-piridin-3-il)-fenilsulfanil]-valerijanska kiselina;-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-valeric acid; -[2,6-difluoro-4-(2-propylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-valeric acid; -[4-(2-ciklopentilsulfanil-piridin-3-il)-fenilsulfanil]-valerijanska kiselina;-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-valeric acid; -[4-(2-ciklobutilsulfanil-piridin-3-il)-fenilsulfanil]-valerijanska kiselina;-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-valeric acid; -[4-(2-ciklobutilmetoksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-valerijanska kiselina; -[4-(2-ciklobutoksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-valerijanska kiselina;-[4-(2-cyclobutylmethoxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-valeric acid; -[4-(2-cyclobutoxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-valeric acid; -[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenoksi]-kapronska kiselina;-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-caproic acid; -[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenoksi]-enantna kiselina;-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-enanoic acid; -[2-fluoro-4-(2-izopropoksi-piridin-3-il)-fenoksi]-valerijanska kiselina;-[2-fluoro-4-(2-isopropoxy-pyridin-3-yl)-phenoxy]-valeric acid; -[4-(2-ciklopentilsulfanil-piridin-3-il)-2-fluoro-fenoksi]-valerijanska kiselina;-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2-fluoro-phenoxy]-valeric acid; -[4-(2-ciklobutilsulfanil-piridin-3-il)-2-fluoro-fenoksi]-valerijanska kiselina;-[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2-fluoro-phenoxy]-valeric acid; -[4-(2-ciklopentiloksi-piridin-3-il)-2-fluoro-fenoksi]-valerijanska kiselina;-[4-(2-cyclopentyloxy-pyridin-3-yl)-2-fluoro-phenoxy]-valeric acid; -[2,6-difluoro-4-(2-metoksi-piridin-3-il)-fenoksi]-buterna kiselina;-[2,6-difluoro-4-(2-methoxy-pyridin-3-yl)-phenoxy]-butyric acid; -[4-(2-aliloksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;-[4-(2-allyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid; -[4-(2-but-2-iniloksi-piridin-3-il)-2,6-difluoro-fenoksi]-buterna kiselina;-[4-(2-but-2-ynyloxy-pyridin-3-yl)-2,6-difluoro-phenoxy]-butyric acid; -[4-[2-(ciklobutoksi)-3-piridil]-2,6-difluoro-fenoksi]kapronska kiselina;-[4-[2-(cyclobutoxy)-3-pyridyl]-2,6-difluoro-phenoxy]caproic acid; -[4-[2-(ciklobutilmetoksi)-3-piridil]-2,6-difluoro-fenoksi]kapronska kiselina;-[4-[2-(cyclobutylmethoxy)-3-pyridyl]-2,6-difluoro-phenoxy]caproic acid; -[4-[2-(ciklopropilmetoksi)-3-piridil]-2,6-difluoro-fenoksi]kapronska kiselina;-[4-[2-(cyclopropylmethoxy)-3-pyridyl]-2,6-difluoro-phenoxy]caproic acid; -[4-(2-ciklobutilsulfanil-3-piridil)-2,6-difluoro-fenoksi]kapronska kiselina;-[4-(2-cyclobutylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]caproic acid; -[4-(2-ciklopentilsulfanil-3-piridil)-2,6-difluoro-fenoksi]kapronska kiselina;-[4-(2-cyclopentylsulfanyl-3-pyridyl)-2,6-difluoro-phenoxy]caproic acid; -[4-(2-ciklopentiloksi-piridin-3-il)-2,6-difluoro-fenilsulfanil]-kapronska kiselina;-[4-(2-cyclopentyloxy-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-caproic acid; -[4-(2-ciklopentilsulfanil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-kapronska kiselina; -[4-(2-ciklobutilsulfanil-piridin-3-il)-2,6-difluoro-fenilsulfanil]-kapronska kiselina; i -[2,6-difluoro-4-(2-propilsulfanil-piridin-3-il)-fenilsulfanil]-kapronska kiselina.-[4-(2-cyclopentylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-caproic acid; -[4-(2-cyclobutylsulfanyl-pyridin-3-yl)-2,6-difluoro-phenylsulfanyl]-caproic acid; and -[2,6-difluoro-4-(2-propylsulfanyl-pyridin-3-yl)-phenylsulfanyl]-caproic acid. 2. Farmaceutska kompozicija kao GPR120 agonisti, koja obuhvata biarilni derivat, njegovu farmaceutski prihvatljivu so ili E- ili Z-izomer, ili R- ili S-izomer prema zahtevu 1, i farmaceutski prihvatljiv nosač.2. Pharmaceutical composition as GPR120 agonists, comprising a biaryl derivative, its pharmaceutically acceptable salt or E- or Z-isomer, or R- or S-isomer according to claim 1, and a pharmaceutically acceptable carrier. 3. Farmaceutska kompozicija za upotrebu u sprečavanju ili lečenju dijabetesa, komplikacija dijabetesa, gojaznosti, nealkoholne masne jetre, steatohepatitisa, osteoporoze ili zapaljenja, koja obuhvata biarilni derivat, njegovu farmaceutski prihvatljivu so ili E- ili Z-izomer, ili R- ili S-izomer prema zahtevu 1, i farmaceutski prihvatljiv nosač.3. A pharmaceutical composition for use in the prevention or treatment of diabetes, complications of diabetes, obesity, non-alcoholic fatty liver, steatohepatitis, osteoporosis or inflammation, comprising a biaryl derivative, its pharmaceutically acceptable salt or E- or Z-isomer, or R- or S-isomer according to claim 1, and a pharmaceutically acceptable carrier. 4. Kompozicija za upotrebu kod snižavanja nivoa glukoze u krvi, koja obuhvata biarilni derivat, njegovu farmaceutski prihvatljivu so ili E- ili Z-izomer, ili R- ili S-izomer prema zahtevu 1, i farmaceutski prihvatljiv nosač.4. A composition for use in lowering blood glucose levels, comprising a biaryl derivative, a pharmaceutically acceptable salt thereof or an E- or Z-isomer, or an R- or S-isomer according to claim 1, and a pharmaceutically acceptable carrier. 5. Postupak za pripremu kompozicije za upotrebu u sprečavanju ili lečenju dijabetesa, komplikacija dijabetesa, gojaznosti, nealkoholne masne jetre, steatohepatitisa, osteoporoze ili zapaljenja, koji obuhvata fazu mešanja biarilnih derivata, njegovih farmaceutski prihvatljivih soli ili E- ili Z-izomera, ili R-ili S-izomera prema zahtevu 1 sa farmaceutski prihvatljivim nosačem.5. A method for preparing a composition for use in the prevention or treatment of diabetes, complications of diabetes, obesity, non-alcoholic fatty liver, steatohepatitis, osteoporosis or inflammation, which includes the phase of mixing biaryl derivatives, its pharmaceutically acceptable salts or E- or Z-isomers, or R- or S-isomers according to claim 1 with a pharmaceutically acceptable carrier. Izdaje i štampa: Zavod za intelektualnu svojinu, Beograd, Kneginje Ljubice 5Published and printed by: Institute for Intellectual Property, Belgrade, Kneginje Ljubice 5
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